144th OMICS Group Conference
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Scientific Tracks & Abstracts
MedChem & CADD-2013 Page 27 Track 1 Day 1 October 15, 2013 1: Rational Drug Designing Session Chair Session Co-Chair Victor J. Hruby Alexander Heifetz University of Arizona, USA Evotec (UK) Ltd., UK
Session Introduction Title: Design and investigation of multivalent ligands for the detection and treatment of diseases Victor J Hruby, University of Arizona, USA Title: Structure based drug discovery for GPCRs: From receptors to ligands Alexander Heifetz, Evotec (UK) Ltd., UK Title: DNA binding polyamides designed against E1, E2 binding sites of HPV DNA show dramatic anti-HPV activity in cell and tissue culture James K Bashkin, University of Missouri-St. Louis, USA Title: Structure-guided design, synthesis, and evaluation of guanine-derived inhibitors of the eIF4E mRNA-cap interaction Xiaoqi Chen, Amgen, USA Title: The design and discovery of CXCR4 chemokine receptor antagonists through incorporation of GPCR-MedChem based fragments Larry Wilson, Emory University and Emory Institute for Drug Development, USA Title: Understanding the essential requirements for success in structure-based design Gregory L Warren, OpenEye Scientific Software, USA Title: Site Identification by Ligand Competitive Saturation (SILCS): Computational approach for the identification and optimization of ligands targeting proteins, RNA and other macromolecules Alexander D MacKerell, University of Maryland, USA Title: Computer-aided design of glucokinase activators Meihua Tu, Pfizer, USA Title: Non-competitive regulation of the human proteasome by natural products and natural product inspired scaffolds Jetze J Tepe, Michigan State University, USA Title: Rational design approaches to find novel ligands targeting the aryl hydrocarbon receptor: successful applications and mechanistic studies William H Bisson, Oregon State University, USA Title: Modulations of protein-protein interactions of EGFRs: Structure, inhibition, dynamics and its implications in breast cancer Seetharama D. Satyanarayanajois, University of Louisiana at Monroe, USA Title: Development of new antibiotics by targeting essential enzymes in bacteria: Structure-based design and simulation studies Concepción González-Bello, Universidad de Santiago de Compostela, Spain Title: Design and synthesis of novel pyrimidone analogues as HIV-1 integrase inhibitors Guisen Zhao, Shandong University, China Title: Synthesis and anti-candida activity evaluation of new [1,2,4] triazolo[3,4-b][1,3,4] thiadiazines Mashooq Ahmad Bhat, King Saud University, Kingdom of Saudi Arabia Title: Newer approaches to the discovery of glitazones Praveen Thaggikuppe Krishnamurthy, JSS College of Pharmacy, India
MedChem & CADD-2013 Page 28 Victor J. Hruby, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Design and investigation of multivalent ligands for the detection and treatment of diseases Victor J. Hruby University of Arizona, USA
evelopment of drugs for the detection and treatment of degenerative diseases such as cancer, prolonged and neuropathic Dpain, diabetes, etc. has proved to be very difficult. Most current treatments are inadequate, treat mostly symptoms, and have toxicities and development of tolerance that prevent effective long term use. Recent genomic and proteomic studies have shown that in many cases the diseases result from multiple changes in the expressed genome. These findings present opportunities for the development of new approaches to drug design and development. In particular it is possible to design multivalent ligands that can address 2 or more targets for the disease state, all in a single molecule. Depending on the nature of the target, different strategies are required so as to assure that each of the pharmacophores can act at their particular targets (receptor, accepter, enzyme, etc.) without interfering with the actions of the other pharmacophore. We illustrate these principles and this new approach for two different diseases. In the first case, we address the problem for designing ligands which can treat the most ubiquitous disease in the world, prolonged and neuropathic pain, without toxic side effects, for which there is no current effective treatment. We have designed bivalent and trivalent ligands that can act as antagonists at neurokinin-1 or bradykinin receptors and/or as agonists at the mu and delta opioid receptors in a single molecule. We can demonstrate that these ligands can treat neuropathic pain in vivo without toxicities or development of tolerance. In another example, we demonstrate the development of novel multivalent scaffolds that can target cancer cells but not normal cells, and thus can be used for the early detection and treatment of cancer.
Biography Victor J. Hruby is a Regents Professor in the Department of Chemistry and Biochemistry at the University of Arizona. He received his Ph.D. at Cornell University in Theoretical Organic Chemistry and did a Postdoctoral studies with Nobel Laureate Vincent du Vigneaud. He has been a Pprofessor at University of Arizona since 1968 where he has joint appointments in the Neuroscience Program, Medical Pharmacology, and Bio5 among others. His research interests are in the chemistry, biophysics, molecular pharmacology, molecular biology of peptide hormones and neurotransmitters and their receptors, transduction systems and in the design, synthesis and bio evaluation of novel ligands for the treatment of degenerative diseases.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 29 Alexander Heifetz et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Structure-based drug discovery for gpcrs: From receptors to ligands Alexander Heifetz and Richard Law Evotec (UK) Ltd., United Kingdom
-Protein coupled receptors (GPCRs) have enormous physiological and biomedical importance, being the primary target of Ga large number of modern drugs. The availability of structural information on the binding site of the targeted GPCR plays a key role in rationalization, efficiency and cost-effectiveness of the drug discovery process. X-ray crystallography, a traditional source of structural information, is not currently feasible for every GPCR or GPCR-ligand complex. This situation significantly limits the ability of crystallography to impact the drug discovery process for GPCR targets in “real-time” and hence there is an urgent need for other practical alternatives. The goal of our research is the generation of GPCR 3D structures by applying integrated experimental-computational methods followed by their application in structure-based drug discovery. This research is done in collaboration with membrane protein molecular dynamics group lead by Dr. Philip Biggin from University of Oxford, UK and Structural-Biology group for membrane proteins lead by Prof. So Iwata from Imperial College London, UK. The research is supported by Royal Society UK and Evotec Ltd. The experimental validation of this research is provided mainly by Evotec within real drug discovery projects. The results of this research will be exemplified by MCH-1R, Orexin-1 and -2 Receptors, 5HT2c and/or other drug-discovery cases.
Biography Alexander Heifetz is a principal scientist at Evotec (UK) Ltd, a drug discovery services company. He provides CADD expert support for drug discovery programs. He obtained his Ph.D. from the Weizmann Institute of Science, Israel, in 2001 under supervision of former Israeli president and Foreign Member of the Royal Society Prof. Ephraim Katzir and Dr. Miriam Eisenstein. He has more than 12 years of experience in drug discovery industry (EPIX Pharmaceuticals and Evotec) and was involved in discovery of 3 clinical drug candidates for treatment of anxiety, major depressive disorder, pulmonary hypertension, and Alzheimer’s disease. He has more than 18 patents, patent applications and a wide range of publications in the area of medicinal chemistry and molecular modelling. Recently, he received the Royal Society Industry Award and established collaboration with academic group of Dr. Phillip Biggin from the University of Oxford, for development of methods for GPCR modelling.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 30 James K. Bashkin, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
DNA-Binding polyamides designed against E1, E2 binding sites of HPV DNA show dramatic anti-HPV activity in cell and tissue culture James K. Bashkin NanoVir, USA
series of polyamides based on pyrrole-imidazole polyamides was designed to interfere with viral protein-viral DNA Ainteractions at the origin of replication of the high risk human papillomavirus types 16, 18 and 31. The specific sites targeted were the E1 and E2 protein binding sites on the viral genomes. The initial library showed hits in cell culture screens. Activity was assessed by qPCR determination of viral DNA 48 h after treatment in cell culture. Dose response curves were determined in all cases, with at least triplicate points. Active compounds were further elaborated and modified in a series of subsequent libraries, with initial optimization achieving many sub-100 nM IC50s and apparent IC50’s as low as 36 nM. Since the three viral genomes are not degenerate for polyamide binding in the target regions, we were surprised to find that a significant number of compounds showed broad-spectrum anti-HPV activity against all three viral subtypes investigated (16, 18 and 31). Although the MWs are high, excellent cell culture activity is seen, in agreement with related studies. Two compounds are in preclinical development and have been scaled up to >6 g. More recently, we have discovered a new class of polyamides functionalized at the N-terminus which are active to IC50s of ca. 10 nM. Most recently, important clues to the mechanism of action have been discovered: HPV-infected cells treated with active compounds show activation of one branch of the DNA Damage Response Pathway, while uninfected cells show no such response.
Biography James K. Bashkin completed his D.Phil. at the age of 24 years from the University of Oxford (U.K.) and postdoctoral studies from Harvard University. He is co-founder and director of chemistry at NanoVir LLC and Professor of Chemistry & Biochemistry at the University of Missouri-St. Louis. He has published more than 60 papers, has 11 issued U.S. patents, and serves as an editorial advisory board member of Chemical Reviews.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 31 Xiaoqi Chen, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Structure-guided design, synthesis, and evaluation of guanine-derived inhibitors of the eIF4E mRNA-cap interaction Xiaoqi Chen Amgen, USA
he eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein Tsynthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds displaying potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC50 of 2.5 M for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point towards the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.
O + Cl HN N O N O H2N N N O O HN - O P OH O P O Me N N N OH O- H HO OH
m7-GMP, eIF4E SPA IC50=14∝M 33, eIF4E SPA IC50=95nM
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 32 Larry Wilson, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
The design and discovery of CXCR4 chemokine receptor antagonists through incorporation of GPCR-medchem based fragments Larry Wilson Emory University and Emory Institute for Drug Development, USA
n the world of G-protein coupled receptor drug research, there have been many profitable developments leading to historical Iand recent therapeutic breakthroughs. The chemokine receptors are a newer addition to the list of the growing number considered as GPCR “druggable” targets with two drugs now approved in this area. Our interest in the chemokine receptor CXCR4 comes from the involvement of this GPCR in immune system complex functions. Designing antagonists of this receptor would result in potential drugs for treatments varying from stem cell mobilization to prevention of HIV virus entry and infection. The recent drug approval of the cyclam AMD3100 illustrates the potential. Our effortts involve the design of new ligands of the CXCR4 receptor based on fragments and chemotypes in a de novo hit-to-lead effort. These fragments were selected based on their frequency of appearance in medicinal chemistry and GPCR small molecule research. This has resulted in the discovery of CXCR4 antagonists containing the tetrahydro-isoquinoline (TIC) and piperazine fragments, which possess nanomolar potencies against the receptor in various bioassays of ligand (SDF-1/HIV) and receptor (CXCR4) involvement. The strategy and design along with the synthesis and biological results will be presented. Also, some computational modeling showing proposed binding modes of these molecules and the CXCR4 receptor will be shown.
Biography Larry Wilson completed his Ph.D. from Emory University and postdoctoral studies from Stanford University. He has served various roles in research and development groups at several large pharmaceutical and small biotech companies. He has over 50 publications, patents, and review articles. He is currently principal scientist at Emory University, where he serves as project leader of the discovery of CXCR4 antagonists for potential treatments in stem cell mobilization, cancer, and HIV infection.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 33 Gregory L. Warren, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Understanding the essential requirements for success in structure-based design Gregory L. Warren Open Eye Scientific Software, USA
e know that for any prediction the quality of the data used to build a model has a direct impact on the quality of the Wpredictions from that model. Developing and validating software for modeling protein-ligand interactions requires protein-ligand structure data; developing and validating high quality software for modeling protein-ligand interactions therefore requires high quality structure data. If predictions from a molecular docking program fail, is the failure the result of poorly developed software, using poor data for the prediction, or the use of poor data invalidation? This presentation will discuss methods to measure the suitability of protein-ligand structure data for docking software validation. Using the recently published iridium data set, it will be shown that a high proportion of structures used for validating docking software in the past are, in fact, entirely unsuitable for this task, but heuristics will be presented that will allow assembly of datasets appropriate for this purpose.
Biography Gregory L. Warren received his Ph.D. in Biochemistry from Massachusetts Institute of Technology, Cambridge, MA. He worked as a postdoctoral fellow at Yale Univeristy in the laboratory of Axel Brunger as part of the development team for the Crystallography & NMR System (CNS) refinement suite. He worked for 8 years as a molecular modeler at Glaxo Smith Kline Pharmaceuticals before moving to Open Eye Scientific Software, Inc., where his work currently includes structure based designand X-ray crystallography applications.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 34 Alexander D. MacKerell, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Site identification by ligand competitive saturation (SILCS): Computational approach forthe identification and optimization of ligands targeting proteins, RNA and other macromolecules Alexander D. MacKerell University of Maryland, USA
omputational ligand design and optimization typically involve a single binding site, single ligand approach that is time Cand resource expensive. Fragment-based methods partially overcome this limitation, but current approaches include approximations with respect to the treatment of solvation and protein flexibility. To overcome these limitations we have developed the site identification by ligand competitive Saturation (SILCS) approach that uses explicit solvent all-atom molecular dynamics simulations to identify binding sites on protein surfaces for functional group classes based on rigorous free energy criteria that include protein flexibility and fragment desolvation. Information from the SILCS approach, termed Frag Maps, are produced in an upfront pre-computed calculation that may be rapidly accessed for the identification of novel ligands that bind to the target macromolecule, for de novo ligand design or for ligand optimization. Visualization of SILCS Frag Maps allows for qualitative ligand design by medicinal chemists while the Frag Maps also may be used for rapid, quantitative estimates of relative free energies of binding. Notably, the SILCS methodology may be applied to occluded binding sites such as those present in G-protein coupled receptors (GPCRs).
Biography Alex D. MacKerell received a Ph.D. in Biochemistry in 1985 from Rutgers University, which was followed by postdoctoral fellowships in the Department of Medical Biophysics, Karolinska Institutet, Stockholm, Sweden and the Department of Chemistry, Harvard University. In 1992 he acquired his faculty position in the School of Pharmacy, University of Maryland where he is currently the Grollman-Glick Professor of Pharmaceutical Sciences and the Director of University of Maryland Computer-Aided Drug Design Center.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 35 Meihua Tu, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Computer-aided design of glucokinase activators Meihua Tu Pfizer Worldwide Research and Development, USA
lucokinase (GK), also termed as hexokinase IV, is a unique isoform of the hexokinase enzymes. It catalyzes the Gphosphorylation of glucose to glucose-6-phosphate. GK plays an important role in the control of whole-body glucose homeostasis by enhancing glucose stimulated insulin release from the pancreatic b-cells and promoting glycogen synthesis in the liver. Compounds that activate GK have been shown to increase hepatic glucose uptake and reduce hyperglycemia in multiple animal models of T2D. Multiple glucokinase activators (GKAs) have been evaluated in the clinic for the treatment of T2D. However, despite the promising efficacy of this mechanism, there has been significant attrition in the clinical development of glucokinase activators, driven by narrow therapeutic windows against hypoglycemia as well as concerns around durability and chemotype-specific safety issues. These issues with early activators have fostered investigations into structurally diverse second generation activators with different biochemical profile to reduce hypoglycemia risk.
Unlike traditional medicinal chemistry binding affinity optimization, enzymatic biochemical profilem (K and Vmax) has been proved to be extremely hard to SAR. In the talk, we will present a computational model that enabled us prospectively design GKAs with desired biochemical profiles that demonstrated reduced hypoglycemia risk.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 36 Jetze J. Tepe, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Non-competitive regulation of the human proteasome by natural products and natural product inspired scaffolds Jetze J. Tepe Michigan State University, USA
ultiple myeloma (MM) is an incurable and fatal type of cancer that affects plasma cells, which will accumulate in the Mbone marrow leading to bone destruction. Although the leading MM drug, bortezomib, is undoubtedly one of the biggest breakthroughs in this field, nearly all patients will become intolerant or resistant within a few years, after which the average survival time is less than one year. The underlining mechanism of resistance to bortezomib has been attributed, in part, to the formation of clusters of mutations in the proteasomes 5 subunit, which prevent drug binding. Unfortunately, since all clinically and second generation proteasome inhibitors proceed via the same mechanism of binding, all of them exhibit high cross- resistance. Thus, proteasome inhibitors that proceed via a different mechanism of action are desperately needed. We will present the total synthesis and biological activity of several natural products and natural product-inspired scaffolds as mechanistically distinct proteasome inhibitors. The heterocyclic, small molecule proteasome inhibitors regulate proteasome activity via a non-competitive mechanism, by binding in a site not previously targeted by any drugs. These non-competitive modulators acts additively with and overcome resistance to classic MM drugs such as bortezomib. The cellular activity of these orally available small molecules translates well in vivo and delayed tumor growth in an MM xenograft model to a similar extent as bortezomib.
Biography Jetze J. Tepe received his Ph.D. from the University of Virginia in 1998 with Prof. Timothy L. Macdonald and continued his post-doctoral studies with Prof. Robert M. Williams at Colorado State University. In 2000, he joined the faculty at Michigan State University where his lab is focused on the synthesis and biological evaluation of heterocyclic natural products. In 2003, he received the American Cancer Research Scholar award and he was the recipient of the Multiple Myeloma Research Foundation Senior Award in 2008 and 2010 and the International Myeloma Senior Award in 2013.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 37 William H. Bisson, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Rational design approaches to find novel ligands targeting the aryl hydrocarbon receptor: Successful applications and mechanistic studies William H. Bisson Oregon State University, USA
he aryl hydrocarbon receptor (AhR) is a ligand activated member of the basic helix-loop-helix (BhLH) family of transcription Tfactors. The AhR is activated by a variety of compounds, both synthetic and natural, including halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and mediates their biological activity. The AhR is a cytosolic transcription factor bound to several co-chaperones. Upon ligand binding, the AhR translocates from the cytoplasm to the nucleus and regulates genes, including several drug metabolizing enzymes that can influence the therapeutic activity of a number of compounds. The AhR regulates proliferation and differentiation of cells. In addition, the AhR induces immunosuppressive regulatory T cells with therapeutic implications in hyperimmune disorders. The role of the AhR has been also studied by us in cancer and in vivo zeebrafish tissue regeneration. Up to now, the AhR-LBD-PASB domain remains experimentally unresolved. Hence, the homology models of the AhR-LBD PASB domain were prepared to identify new AhR ligands by virtual ligand screening. Successful applications in finding novel agonists, selective modulators (sAhRM) and full antagonists of the AhR will be described. Recent mechanistic studies using computational molecular simulations on the AhR models will be reported. The results obtained demonstrate that in the absence of experimentally resolved structures, computational chemogenomics techniques are still a successful tool in the hands of interdisciplinary teams for the discovery of novel AhR-targeted therapeutics.
Biography William H. Bisson completed his Ph.D in 2003. at Medicinal and Computational Chemistry at the ETH Zurich, Switzerland. In 2004, he joined as a Research Fellow at the Scripps Research Institute in La Jolla, CA. Later in 2006, he started as a Research Associate at the nearby Sanford-Burnham Medical Research Institute. In 2008 he joined as a Research Associate at the Oregon State University and in 2010 he came back to Switzerland, at the University of Geneva as Senior Research Scientist. Currently, he is Assistant Professor at Oregon State University working successfully in inter- disciplinary projects mostly in cancer using computational chemogenomics.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 38 Seetharama D. Satyanarayanajois, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Modulations of protein-protein interactions of EGFRs: Structure, inhibition, dynamics and its implications in breast cancer Seetharama D. Satyanarayanajois University of Louisiana at Monroe, USA
roteins interact with each other in a highly specific manner, and these specific interactions play key roles in many cellular Pprocesses. In normal life processes, these protein-protein interactions are well coordinated to perform the functions of the cells. Any deregulation of this process can lead to the development of many diseases. HER2, a member of EGFR proteins, is overexpressed in approximately 30% of breast cancers. HER2 is known to form heterodimers with other EGFR proteins such as EGFR and HER3, and is a major therapeutic target in breast cancer treatment. We have designed a number of peptidomimetics to target domain IV of HER2 protein to inhibit HER2-mediated signaling. One of such peptidomimetics, compound 5, exhibited
antiproliferative activity with IC50 values in the nanomolar range against HER2 overexpressing breast cancer cell lines SKBR-3 and BT-474. To further investigate the structure-activity relationship of peptidomimetics several analogs were designed. Some of these analogs exhibited antiproliferative activity against breast cancer cell lines in nanomolar concentration. Path Hunter and proximity ligation assay results indicated the inhibition of HER2 heterodimerization by these compounds. Furthermore, in vivo studies in xenograft model of breast cancer suggested that these compounds delayed the breast tumor growth. Compound 5 was conjugated with BODIPY fluorescent probe to evaluate the binding and internalization of 5. These results suggest that small peptidomimetic molecules can inhibit protein-protein interactions of EGFRs, which can be therapeutically useful for controlling breast cancer.
Biography Seetharama D. Satyanarayanajois is an Associate Professor in the department of basic pharmaceutical sciences, college of pharmacy, University of Louisiana at Monroe. He obtained his Ph.D. degree in the molecular biophysics unit at the Indian Institute of Science, Bangalore, India. During the past several years, he has worked extensively on the design of peptide/peptidomimetic molecules to target proteins that are important in human diseases using computational and experimental techniques. He is the author and co-author of more than sixty publications. He has edited a special series in Methods in Molecular Biology, Drug Design and Discovery -Methods and Protocols.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 39 Concepcion Gonzalez-Bello, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Development of new antibiotics by targeting essential enzymes in bacteria: Structure-based design and simulation studies Concepcion Gonzalez-Bello University of Louisiana at Monroe, USA
he possible development of new antibiotics whose mode of action is based on the selective and effective inhibition of an Tessential route in bacteria that does not have any counterpart in human cells, the shikimic acid pathway, will be discussed. In particular, the talk will be focused in the inhibition of the third and the fifth enzyme of this pathway, type II dehydroquinase and shikimate kinase. Both enzymes are essential in certain pathogenic microorganisms, such as Mycobacterium tuberculosis and Helicobacter pylori, which are responsible for tuberculosis and stomach cancer, respectively. The key interactions of the substrate and product binding and the enzyme movements that are essential for catalytic turnover of both enzymes have been investigated by structural and computational studies. Based on the mode of action of the enzyme, molecular modeling, dynamic simulations and structural studies and by creating favorable interactions with key residues in the enzymatic mechanism several potent inhibitors were designed and identified. Some of them are analogues of the natural substrate, and the others are mimics of the enzyme reaction intermediate.The crystal structures of enzyme/inhibitors complexes reveal an important change in the conformation and flexibility of the loop that closes over substrate binding. Our results on this project will be presented.
Biography Concepcion Gonzalez-Bello has obtained her Ph.D. at the University of Santiago de Compostela (USC, Spain) in 1994. She did two predoctoral stays in the University of Gent (Belgium) with Prof. Vandewalle and in the Scripps Research Institute (USA) with Prof. Nicolaou. After three years of postdoctoral stay in the University of Cambridge (UK) with Prof. Chris Abell, she joined USC as an Assistant Professor, and was promoted to Associate Professor in 2003 and obtained the Spanish habilitation to full Professor in 2011. She is a member of the ChemMedChem International Advisory Board and has published about 50 papers in reputed journals.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 40 Guisen Zhao et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Design and synthesis of novel pyrimidone analogues as HIV-1 integrase inhibitors Guisen Zhao1, Shenghui Yu1, Tino Wilson Sanchez2 and Nouri Neamati2 1Shandong University, China 2University of Southern California, USA
series of novel pyrimidone analogues have been designed and synthesized as HIV-1 integrase (IN) inhibitors. This study Ademonstrated that introducing a substituent in the N1-position of the pyrimidone scaffold does not significantly influence IN inhibitory activity. Molecular docking studies showed these compounds could occupy the IN active site and form pi-pi interactions with viral DNA nucleotides DC16 and DA17 to displace reactive viral DNA 3'OH and block intasome activity. Keywords: HIV-1, Integrase inhibitors, Pyrimidone analogues.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 41 Mashooq Ahmad Bhat, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Synthesis and anti-candida activity evaluation of new [1,2,4] triazolo[3,4-b][1,3,4] thiadiazines Mashooq Ahmad Bhat King Saud University, Kingdom of Saudi Arabia
andida species have emerged as the most common cause of systemic fungal infections worldwide over the last two decades. C1,2,4 - triazole moieties have been incorporated into a wide variety of therapeutically interesting drug candidates and antimycotic ones such as fluconazole, itraconazole and voriconazole. The mercapto and thione substituted 1,2,4- triazol ring system have been reported to possess a variety of biological activities such as antibacterial , antifungal, anti-tubercular, anticancer, diuretic and hypoglycemic. The recent literature survey revealed that a special attention was given to those incorporating N-C-S linkage as in the skeleton of the 1,2,4 -triazolo[3,4-b][1,3, 4]thiadiazine derivatives, which proved to have promising biological activities such as antiviral, anti-HIV, CNS stimulant and antifungal. Studies have also confirmed that triazolothiadiazine derivatives possess anti-Candidal activity. Designing new drugs is based on development of hybrid molecules by combining different pharmacophore fragments in a single structure, which may lead to compounds with interesting biological activities. Herein we describe the synthesis of new triazolothiadiazine derivatives, which were tested, in vitro against eleven species. Treatment of 1,2,4-triazole-5-thione derivative 3 with hydrazonoyl chlorides (4a-h) in refluxing ethanol, in the presence of triethylamine, afforded compounds identified as (7Z) -7-[2-substituted phenyl hydrazinylidene] - 6-methyl -3- (pyridine - 4 -yl) -7H-[1,2,4] triazolo[3,4-b][1,3, 4] thiadiazines (5a-h). All compounds were tested in vitro against eleven Candida species and compared with itraconazole. Among these compounds 5a, 5c, 5e and 5g exhibit the highest inhibitory activity against the Candida species at 6.25 µg/ml. This outcome confirms that phenyl, p- methoxy, p-chloro and p-sulfonamido phenyl groups on triazolothiadiazine ring may have a considerable effect on antifungal activity againstCandida species. The compounds with p-bromophenyl (5d) and p-flourophenyl (5f) substituents exhibit inhibitory activity against Candida species at 12.5 µg/ml. The compounds with ortho methyl and p-methyl phenyl substituents were devoid of activity upto 100 µg/ml.
Biography Mashooq Ahmad Bhat has completed his Ph.D. from Hamdard University, New Delhi, India in 2008. Currently he is working as Assistant professor in College of Pharmacy, King Saud University, Riyadh, KSA. He has published more than 25 papers in journals of international repute. He is serving as reviewer of many reputed journals of medicinal chemistry. His area of research is structure based drug design as anticonvulsants and anti-tubercular agents. He has published many single crystal X-ray reports of the synthesized compounds.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 42 Praveen Thaggikuppe Krishnamurthy, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Newer approaches to the discovery of glitazones Praveen Thaggikuppe Krishnamurthy JSS College of Pharmacy, India
hiazolidines (TZDs) or glitazones are one of the important classes of insulin sensitizers used in the management of type 2 Tdiabetes mellitus. These agents, however, suffer from some serious side effects such as fluid retention, weight gain, congestive heart failure, bone fracture and possibly bladder cancer, which resulted in their withdrawal from clinical use. The TZDs that were withdrawn from the clinical use were developed at the time when enough scientific data were not available on the structure and the transcriptional mechanisms of peroxisome proliferator activated receptors (PPARs). Recent advances in the understanding of structure and function of PPARs, however, has led to more rationalized approaches to develop these agents. This presentation discusses the various approaches that have been made to develop newer glitazones devoid of the problems associated with current TZDs. These approaches are based on the structural considerations of both the ligands and the receptors and also on the profile alterations of the ligands.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 43 Track 2 Day 1 October 15, 2013 2: Computer-Aided Drug Design and Structure Determination Session Chair Session Co-Chair Istvan J. Enyedy Nicolas Moitessier Biogen Idec, USA McGill University, Canada
Session Introduction Title: New approaches to “Hit” optimization Istvan J. Enyedy, Biogen Idec, USA Title: Accurate binding site models can be derived from low quality PDB files using an empirical geometry based force field Colin McMartin, Thistlesoft, USA Title: Integrating computational approaches into high throughput screening for rational drug discovery Xin hu, National Center for Advancing Translational Sciences, National Institutes of Health, USA Title: Using side-chain models derived from atomic resolution X-ray crystallography to develop force fields which can predict global energy minimum geometries Regine S. Bohacek, BostondeNovo, USA Title: Forecaster: A computational tool for drug design and discovery developed by experimentalists for experimentalists Nicolas Moitessier, McGill University, Canada Title: Genes to Leads: A rational structure guided lead discovery technology that works for both enzymes and protein-protein interaction targets Kal Ramnarayan, Sapient Discovery, LLC, USA Title: Discovery of highly-potent and selective inhibitors for the ABCG2 transporter Achene Boumedjel, Université Joseph Fourier de Grenoble, France Title: Predictive application of bioisostere transformations to identify novel high quality compound ideas Matthew Segall, Optibrium Ltd., UK Title: Novel sildenafil analogues: Possible drugs for increased sensitivity to chemotherapeutic agents Aina Westrheim Ravna, University of Tromso, Norway Title: Structural insights of SIR2 proteins from T. cruzi as promising targets to fight against Chagas disease Alessandra Nurisso, University of Geneva-University of Lausanne, Switzerland Title: Stratification of surface lysine residues of bovine testicular hyaluronidase on the base ofits3D structure model: Computer aided drug designing of chondroitin sulphate modified enzyme derivative Alexander V. Maksimenko, Institute of Experimental Cardiology, Russia
MedChem & CADD-2013 Page 45 Istvan J. Enyedy, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
New approaches to “hit” optimization Istvan J. Enyedy Biogen Idec, USA
arget structure-based “hit” optimization in a drug discovery project is challenging from the computational point of view. TScoring functions cannot predict binding affinity, thus computational chemists must use their intuition or prior knowledge about the target class to prioritize compounds for synthesis. As the pharmaceutical industry targets novel protein classes, computational chemists must use software to build their know-how about the protein. The talk will focus on how we can use solvent mapping and information from co-crystal structures in guiding docking and scoring. Test results of this procedure on seven kinases using the HYBRID docking protocol from Open Eye will be shown.
Biography Istvan J. Enyedy has been involved in new target evaluation, hit finding, and hit-to-lead optimization projects for several types of target classes using both ligand and structure-based methods since the past 14 years. He is co-author on more than 30 publications and 9 patents/applications. He received his Ph.D. in 1998 at Catholic University of America, Washington DC, and did postdoctoral training in Dr. Shaomeng Wang’s group at Georgetown University Medical Center, Washington DC. Between 2001 and 2008 he worked at Bayer Pharmaceuticals, West Haven CT and Novartis Institutes for Biomedical Research in Cambridge MA. Since August 2008 he has been working at Biogen Idec, in Cambridge MA.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 46 Colin McMartin et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Accurate binding site models can be derived from low quality PDB files using an empirical geometry based force field Colin McMartin1 and Regine S. Bohacek2 1Thistlesoft, USA 2BostondeNovo, USA
new geometry force field based on atomic resolution regions PDB structures was recently published1 . The new force field Ahas now been tested in many examples not included in the original study. It is very successful in preserving geometries and computed energies in packed small molecule crystals and in atomic resolution regions of PDB structures. When applied to low quality PDB structures the force field causes small movements of those atoms with high energy features and anomalous geometries. This results in structures with energies and geometries similar to those found at high resolution. In the present work the force field was applied to binding site models selected from the entire resolution range of the PDB. A binding site model consists of a ligand and residues in close contact. Binding site models are selected if all atoms a reported, have unique coordinates, have Boltzmann factors less than 80 A2 and do not have non-bonded clashes. These criteria are clear and easily applied and thousands of models satisfying these criteria have been found. Application of the force field to these models produces optimized models with similar energy and geometry profiles to those found in high resolution X-ray models. This process has provided a large set of consistent binding site models. The set contains many series of models where a unique binding site (100% sequence homology) is complexed with a variety ligands. This data is ideal for a broad empirical study of the effects of ligands on binding site flexibility. Tools for using this data base for exploring binding site flexibility are given in a poster at meeting2.
Biography Colin McMartin owns a computational soft-ware company, FLO/QXP, which specializes in force field development/application. A recent publication based on atomic resolution protein crystal geometries describes a new geometry force field as well as methods for developing complete models with explicit water and hydrogen bond networks suitable for structure based design.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 47 Xin Hu, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Integrating computational approaches into high throughput screening for rational drug discovery Xin Hu National Institutes of Health, USA
igh-throughput screening (HTS) and structure/ligand-based virtual screening (VS) are two well-established techniques Hthat are widely used in drug discovery. Progress on the applications of virtual and biological screening is currently moving towards the integration of these two synergistic approaches. Given the fact that more than 86% of the molecular targets in Pub Chem have related structural information in PDB, it is expected that a combined campaign with HTS and VS can be conducted in parallel to maximize their output and greatly improve the screening efficiency. Various computational approaches have been introduced to foster the screening process and data integration; however, it remains a challenging task to integrate these two distinct approaches efficiently in practice. Here we present case studies in finding small molecule inhibitors of bacterial virulence effectors combining HTS and computational approaches including molecular modeling and binding-site predication, ligand- based QSAR and pharmacophore search, structure-based docking and virtual screening, MD simulation and binding free energy calculations, and ADME/T modeling. To facilitate the comparative analysis and visualization of VS and HTS data, we developed a web-based tool that integrates the rich biochemical assay data of HTS, 3D structures of protein targets, and predicted protein- ligand binding models from VS into a unified system for efficient data mining. A user-friendly graphical user interface allows users to visualize and manipulate the multidimensional data in an interactive environment, providing a useful informatics platform for computer-aided rational drug discovery.
Biography Xin Hu received his B.S. in Pharmacy in 1991 from Beijing University, Ph.D. in Pharmaceutical Sciences in 2003 from North Dakota State University, followed by a postdoctoral training at The Rockefeller University. Currently, he is a research scientist at the National Center for Advancing Translational Sciences, National Institutes of Health (NCATS/NIH).
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 48 Regine S. Bohacek et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Using side-chain models derived from atomic resolution X-ray crystallography to develop force fields which can predict global energy minimum geometries Regine S. Bohacek1 and McMartin C2 1BostondeNovo, USA 2Thistlesoft, USA
rediction of low energy conformers in a protein is a challenging computational problem because the energy depends on a Plarge number of intermolecular interactions. Each conformer will experience a very different set of interactions and the energies of these must be determined accurately to find a minimum. The energies depend on the accuracy of the geometry and the competence of the mathematical modeling of potential energy. To learn how to compute these energies, we are exploring energy functions using a large set of models of amino acids models with diverse contact shells. The models are derived from atomic resolution protein crystallography and are extremely accurate. The initial test set consists of models of amino acids plus neighboring residues. Conformers are generated using a modified allegrow. These are tested using energy minimization using an empirical geometry optimization force field and additional energy terms. Preliminary results show that results for polar side- chains depend on the solvation state. Published methods for adding explicit solvent and creating optimum hydrogen bonding networks to each conformational model are being tested.
Biography Regine S. Bohacek is founder and owner of Boston Denovo.com and has published extensively in the field of computational chemistry with a particular interest in de novo methods and structure based design
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 49 Nicolas Moitessier, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Forecaster: A computational tool for drug design and discovery developed by experimentalists for experimentalists Nicolas Moitessier McGill University, Canada ver the last ten years we have been developing software for drug design and discovery. In order to make them available to Oexperimentalists, efforts were made to automate the processes, thus reducing errors and the need for extensive training. Thus each individual piece of software, including FITTED; a docking program which considers displaceable water molecules, protein flexibility and covalent binding, IMPACTS; a program for prediction of sites of metabolism of drugs and REACT; a tool for virtual combinatorial chemistry have been integrated into a web-based plateform FORECASTER. This platform has then been applied to real case studies. We will present the development of this computational package as well as existing experimental applications and validation. Among these applications are the computer-aided design and synthesis of prolyl oligopeptidase inhibitors that demonstrated high inhibitory potency in cell-based assays and the experimental determination of their major metabolites initially predicted by IMPACTS.
Biography Nicolas Moitessier received his Ph.D. from Université Henri Poincaré (Nancy, France). In 1998, he moved to Montréal where he joined Prof. Hanessian group for post doctoral work. In 2001, he moved back to Nancy to start an academic career then back to Montréal in 2003 (McGill University). His current research interests integrate software development, computational chemistry and organic/medicinal chemistry. He has published over 55 papers and has founded Molecular Forecaster in 2010. In 2008, he received the first Reginald Fessenden Professorship in innovation for the development of the Forecaster drug discovery platform. In 2009, he was awarded the Astra Zeneca Award in Chemistry.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 50 Kal Ramnarayan, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Genes to leads: A rational structure guided lead discovery technology that works for both enzymes and protein-protein interaction targets Kal Ramnarayan Sapient Discovery, LLC., USA
he entire life sciences industry is focused on only a few hundred protein targets for drug discovery. There are potentially Tmany more novel targets, not only human proteins but also those present in infectious organisms likely to be relevant targets for important new drugs. The abundance of potential drug targets is a challenge for the pharmaceutical and biotech companies that have to focus their resources. At least 50% of all targets that go into HTS screens do not generate significant leads and hence other cost-effective technologies are required to generate novel lead molecules. We have developed a structure-based approach to develop lead molecules in 60 to 90 days, which has resulted in validated lead molecules for a diverse set of drug targets including targets that are involved in protein-protein interaction. Essential ingredients of the technology are: X-ray crystallography, protein modeling, virtual screening, docking and scoring. In this presentation we would like to discuss our technology with specific application examples in protein-protein interactions.
Biography Kal Ramnarayan is the founder, President, Chief Scientific Officer of Sapient Discovery. Previously, he co-founded Structural Bioinformatics, Inc. and Cengent Therapeutics. Prior to Structural Bioinformatics, Inc., he was head of Computational Chemistry at Immuno Pharmaceutics Inc., where he designed numerous drug leads, including highly specific endothelin; a receptor antagonists. This became Sitaxsentan, currently in Phase III clinical development by Encysive Pharmaceuticals. He holds a Ph.D. in Molecular Biophysics from the Indian Institute of Science, Bangalore and has multiple papers and patents and several other patents pending. He is also co-founder of Focus Synthesis, LLC, in San Diego.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 51 Ahcene Boumendjel, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Discovery of highly-potent and selective inhibitors for the ABCG2 transporter Ahcène Boumendjel Université Joseph Fourier de Grenoble, France
verexpression of multidrug ABC transporters in cancer cells alters anticancer drugs efficacy by reducing their accumulation Oin the intracellular compartment. One of the three ABC transporters being largely involved in resistance of cancer cells toward treatments is the breast cancer resistance protein (BCRP/ABCG2). Overcoming multidrug resistance (MDR phenotype) against anticancer drugs is a challenging problem. One of the strategies to overcome MDR can be achieved through effective inhibitors of the multidrug ABC transporters involved in the MDR. In the present communication we will shed light on our recent discovery of highly potent, non-toxic and selective inhibitors of ABCG2 transporter. A special focus will be made on 5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl) ethyl-1-carbonyl)-4H-chromen-4-one, namely MBL-II-141. The latter inhibits ABCG2 with high affinity (IC50=0.11 μM) with very low cytotoxicity, giving a markedly high therapeutic index. MBL-II-141 is highly selective for ABCG2 versus other transporters and constitutes a good candidate for in vivo chemosensitization of tumors. The design, synthesis, in vitro and our latestin vivo studies will be presented.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 52 Matthew Segall et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Predictive application of bioisostere transformations to identify novel high quality compound ideas Matthew Segall1, James Chisholm1, John Barnard2, Julian Hayward2, Edmund Champness1, Chris Leeding1, Hector Garcia1 and Iskander Yusof1 1Optibrium Ltd., UK 2Digital Chemistry Ltd., UK
e will describe how the principle of bioisosterism can be applied, in combination with predictive modelling and multi- Wparameter optimisation, to quickly search for new, high quality compound ideas and optimisation strategies. Bioisosteres are functional groups which have similar physical or chemical characteristics and hence similar biological effects. The relationships between bioisosteres may be encoded as molecular transformations and automatically applied to new compounds to generate novel compound structures that are likely to preserve the required biological activities. In silico models can be applied to predict the properties of the resulting structures, such as ADME and physicochemical characteristics. These data can, in turn, be integrated using a multi-parameter optimisation approach to prioritise those ideas that are most likely to achieve a required property profile. To illustrate this, we will discuss how the BIOSTER™ database of >20,000 precedented bioisostere transformations and molecular modifications resulting from alternative analogue design techniques has been integrated with the StarDrop™ software. We will describe example applications in drug discovery, including lead hopping and patent protection.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 53 Aina Westrheim Ravna, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Novel sildenafil analogues: Possible drugs for increased sensitivity to chemotherapuetic agents Aina Westrheim Ravna University of Tromso, Norway
he phosphodiesterase 5 (PDE5) inhibitor sildenafil (Viagra ®) also inhibits transport of chemotherapeutic agents out of cancer Tcells via human ATP-binding cassette (ABC) transporters. Attempts to develop ABCB1 (P-glycoprotein) inhibitors have been ongoing for more than 30 years, but because of toxic effects and lack of desired effect of the compounds, none of these have reached the marked yet. Studies have shown that sildenafil increases the intracellular level of the anticancer agents such as paclitaxel, 5-fluorouracil, methotrexate, cisplatin, oxaliplatin and doxorubicin by inhibiting a variety of ABC transporters (ABCB1, ABCC4, ABCC5 and ABCG2), thereby sensitizing cancer cells to these anticancer agents. Furthermore, it has been shown that several ABC transporters are overexpressed in several types of cancer cells and that sildenafil can inhibit tumor growth without cytotoxic agents present. We have identified sildenafil analogues using virtual ligand screening (VLS) and tested them for ABCC5 transporter efflux using inside-out vesicles (IOV). Seven compounds were more potent than sildenafil, and the two most potent showed K(i) of 50-100 nM. These novel sildenafil analogues may be more effective for inhibiting ABC transporter efflux, and the side effects may be fewer. However, it is still too early to say whether the sildenafil analogues can reverse multidrug resistance mediated by ABC-transport in the clinic, but it appears that such compounds may have the potential to improve the therapeutic results of chemotherapy.
Biography Aina Westrheim Ravna has completed her Ph.D. at the age of 31 years from the University of Tromsø and postdoctoral studies from the University of Tromsø, including research stays at the Scripps Research Institute and UCSD, La Jolla, USA. She is currently an Associate Professor at the University of Tromsø. She has more than 30 publications.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 54 Alessandra Nurisso, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Structural insights of SIR2 proteins from T. cruzi as promising targets to fight against Chagas disease Alessandra Nurisso University of Geneva-University of Lausanne, Switzerland
rypanosoma cruzi is a protozoan pathogen responsible for Chagas disease. Current therapies rely only on a very limited Tnumber of drugs, most of them inadequate because of severe host toxicity or drug-resistance phenomena. In order to find therapeutic alternatives, the identification and the study of new biotargets is highly recommended. Recent findings suggested that the inhibition of the silent-information regulator 2 (SIR2)-like proteins, commonly called sirtuins, can cause kinetoplast alterations and cell cycle arrest of the parasite. Therefore, these parasitic sirtuins have emerged as promising new anti-parasitic targets. In the absence of crystallographic data, reliable homology models of sirtuins SIR2rp1 and SIR2rp3 from T. cruzi have been generated. In silico structural analyses revealed important features for the design of novel and selective candidate drugs. Moreover, a library of phytochemicals with a growth inhibitory activity against T. cruzi has been screened against the modeled sirtuins, highlighting the potential mechanism of action of four trypanocidal natural compounds. Taken together, this information on T. cruzi sirtuins may be useful in the research of novel therapeutic strategies against Chagas disease.
Biography Alessandra Nurisso graduated from the University of Turin (Italy) with a Master Degree in Industrial Pharmacy in 2006. She then completed her Ph.D. in Structural Biology and Nanobiology from the University of Grenoble (France) as a Marie-Curie fellow. In 2010, she joined the Pharmacochemistry laboratory of the School of Pharmaceutical Sciences of the University of Geneva (Switzerland), working two years as a post-doctoral fellow. She is currently Assistant Lecturer at the School of Pharmaceutical Sciences and also the winner of the Scholarship of Excellence of the University of Geneva (Switzerland), working on inter-disciplinary projects related to epigenetics.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 55 Alexander V. Maksimenko et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Stratification of surface lysine residues of bovine testicular hyaluronidase on the base of its 3D structure model: Computer aided drug designing of chondroitin sulphate modified enzyme derivative Alexander V. Maksimenko and Robert S. Beabealashvili Institute of Experimental Cardiology, Russia
ntegrity of vascular wall has been underpinned with double protective layer consisting in endothelial cells and their glycocalyx. IThe injury of vascular wall begins with endothelial glycocalyx degradation. Besides synthesis de novo, the regulators of glycocalyx state are reactive oxygen species, proteolytic and glycosidase enzymes. The latters determine the catabolism of glycosaminoglycan part of glycocalyx. Obstacles of glycosidase study are dealt with niggardly data about these mammalian biocatalysts, their low concentration in organism, small stability, deficiency of structural information. The obtaining of crystal structure of hyaluronidases helps to overcome the mentioned above hindrances. We used as archetype of the obtained earlier crystal structure of human hyaluronidase-1 in order to construct 3D model of bovine testicular hyaluronidase (BTH). Superposition of 3D BTH model with 3D structure of human hyaluronidase-1 was quite satisfactory, while with 3D structure of bee venom hyaluronidase had some discrepancies (including the presence of epidermal growth factor-like domain in BTH). The active site of 3D BTH model was indicated as well as sorption complex between BTH and minimal substrate (hyaluronan hexamer) and positions of charged amino acid residues (mainly Lys, Asp, Glu). The surface Lys residues were stratificated according to their access for chemical modification (Lys of first, second, third access level and unproductive residues for Lys modification) due to analysis of Lys microenvironment. The destination of BTH modification is the production of stabilized enzyme forms for medical application. According to experimental results, the covalent complex between BTH and chondroitin sulphate (CHS) is more preferable as compared to complexes with other glycosaminoglycans. CHS modified BTH covalent complexes (BTH-CHS) were constructed in silico with different degree of Lys modification (on the base of 3D BTH model). Moreover, the 3D model of BTH-CHS was constructed with practically full modified/blocked Lys residues. According to experimental data, such BTH-CHS conjugate had molecular mass 180 kDa and more and it was perspective for medical use. From in silico point of view, 140 kDa molecular mass of this conjugate was enough already for fully blockade of Lys residues. The 3D position of CHS chains around BTH globule can be multiform. The fully blockade of surface Lys residues can gain in silico with two CHS chains (m.m. 35-50 kDa) or with one CHS chain (m.m. 120-140 kDa). In latter case, BTH globule is located in CHS coat except two sites only without Lys residues. One of these sites is the area around active site of BTH. Such in silico results are agreed with appreciable remain endoglycosidase activity of BTH (68-78%) after its deep modification by CHS with different molecular mass. The topography of Lys residues stipulates the preservation of substrate access to active site of modified BTH that determines the Lys residue selection for development of modified enzyme derivatives.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 56 Track 3, 4, 6 & 8 Day 2 October 16, 2013 3: Quantitative Structure-Activity Relationships 4: Drug Development and Delivery System 6: Drug Interactions 8: Pharmacognosy Session Chair Session Co-Chair Tatsuya Takagi Cesar M. Compadre Osaka University, Japan University of Arkansas for Medical Sciences, USA
Session Introduction Title: In silico screening for anti-HPV agents using docking studies Tatsuya Takagi, Osaka University, Japan Title: The development of the tocoflexols, a series of novel vitamin E analogues with enhanced bioavailability Cesar M Compadre, University of Arkansas for Medical Sciences, USA Title: New polymeric “ruthenium-cyclopentadienyl” complexes for drug delivery in cancer therapy Andreia Valente, Universidade de Lisboa, Portugal Title: Unraveling the human multidrug resistance p-glycoprotein poly-specificity Pierre Falson, Institute of Biology and Chemistry of Proteins, France Title: PK modulation of haptenylated peptides via non-covalent antibody complexation Stefan Dengl, Roche Diagnostics GmbH, Germany Title: Tumour active plant derived compounds in combination with targeted therapy towards overcoming drug resistance in ovarian cancer Fazlul Huq, The University of Sydney, Australia Title: Designed monofunctional platinums found to have significant antitumor activity Laila Arzuman, The University of Sydney, Australia Title: A phytochemical and biological investigation of Aloe grandidentata Salm-Dyck Taghreed Abdou Ibrahim, King Saud University, Saudi Arabia Title: Docking guided QSAR study on a series of N-acetamideindolecarboxylic acid derivatives acting as HCV NS 5B polymerase inhibitors Vaishali M. Patil, Bharat Institute of Technology, India
MedChem & CADD-2013 Page 57 Tatsuya Takagi, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
In silico screening for anti-HPV agents using docking studies Tatsuya Takagi and Norihito Kawashita Osaka University, Japan
PV (human papilloma virus) is known as one of the papillomavirus family which is able to infect humans. For more than H90% of cervical cancer, especially squamous cell carcinoma, HPV infection appears to be a necessary factor. Although HPV vaccination was recommended in almost all developed countries, including JAPAN, very recently, serious adverse events were reported. Thus, anti-HPV agents should be developed in order to prevent many types of cervical cancers. However, since more than 120 types of HPVs have been identified, it is not easy to inhibit the tumor promoting activities of all carcinogenic HPVs. In this study, we tried to develop HPV E6 protein inhibitors using in silico screening, especially, docking studies. The obtained agents are not for anti-cancer drugs but for in vitro studies which can reveal whether E6 protein inhibitors are capable of suppressing canceration of HPV infected cells. If the inhibitors have such activities, it is not impossible to develop anti-HPV drugs for almost all types of carcinogenic HPVs. We applied two kinds of methods: one is an ordinal in silico screening using docking studies, and the other is a pharmacophore screening plus docking studies using the co-crystal structure of HPV E6 protein and PDZ domain. We obtained some lead chemical structures, which are appeared to be effective for revealing the mechanism of canceration of HPV infected cells, using above two kinds of methods.
Biography Tatsuya Takagi has completed his Ph.D. at the age of 32 years from Osaka University.At that time, he had been a research assistant (this position corresponds to Assistant Professor in the USA) of School of Pharmaceutical Sciences, Osaka University for 5 years. Then, since 1993, he had worked for the Genome Information Research Center, Osaka University as a lecturer until he became a professor of Graduate School of Pharmaceutical Sciences, Osaka University in 1998. He has published more than 100 papers in reputed journals and serving as avice deputy chairman of Division of Structure-Activity Relationship of the Pharmaceutical Society of Japan.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 58 Cesar M. Compadre, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
The development of the tocoflexols, a series of novelvitamin E analogues with enhanced bioavailability Cesar M. Compadre University of Arkansas for Medical Sciences, USA
itamin E is composed of two series of closely related compounds, tocopherols and tocotrienols; which show a widely varying Vdegree of biological effectiveness. In recent years, the tocotrienols have gained considerable attention because of their beneficial effects in areas such as radiation protection, cholesterol reduction and cancer treatment and prevention. Unfortunately, the potential of the tocotrienols has been hampered because their very short circulation half-life severely limits their bioavailability. Using state-of-the-art computational techniques, we have developed the tocoflexols, which are designed to overcome the limitations of the tocotrienols. This was achieved by a novel approach in which we created analogues that more effectively use the natural mechanism of retention of vitamin E components in the body. Specifically this was accomplished by designing compounds that are better accepted by alpha-tocopherol transfer protein, the liver enzyme that controls the circulation levels of vitamin E. By maintaining the bioactivity of the tocotrienols while achieving enhanced bioavailability, these compounds may have a strong potential as therapeutic agents. Structural modification of drugs to take advantage of endogenous transport systems is a novel and intriguing concept whose potential is just starting to emerge. Successful demonstration of its usefulness in this application is likely to encourage development of similar strategies for the future drug design and development in other areas of biomedical sciences.
Biography Cesar M. Compadre has extensive research experience, on the development of bioactive compounds based on naturally occurring compounds, and on the use of molecular modeling in drug design and structure-activity studies. He has published over papers and over 70 patents related to the development of bioactive compounds, and one FDA approved antimicrobial technology. He has a B.S Pharm degree, and obtained his Ph.D. degree in Medicinal Chemistry and Pharmacognosy, from the University of Illinois at Chicago. He conducted postdoctoral research on structure- activity relationships studies using molecular modeling at the University of Illinois and at Pomona College working with Professor Corwin Hansch. Additionally, he had a sabbatical experience at NASA Ames Research Center in computer modeling. At the University of Arkansas for Medical Sciences he established and directs the molecular modeling facility. He has extensive research collaborations with many scientists locally, nationally and internationally.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 59 Andreia Valente et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
New polymeric “ruthenium-cyclopentadienyl” complexes for drug delivery in cancer therapy Andreia Valente1, M. Helena Garcia1, Fernanda Marques2 and Philippe Zinck3 1Faculdade de Ciências da Universidade de Lisboa, Portugal 2Unidade de Ciências Químicas e Radiofarmacêuticas, Portugal 3ENSCL, UCCS, CCM, France
ne of the main problems associated with chemotherapy is the high noxious side effects caused by the lack of selectivity, i.e., Othe drugs are not specific to the cancer cells. The ideal situation is to achieve a high degree of selectivity where the drug might be only delivered to the tumour without affecting the healthy tissues. In this frame, polymeric metal complexes (PMCs) put forward an important contribution to the drug-delivery research in cancer therapy, using polymers as drug carriers. The great advantage is the easier accumulation of polymers in the cancer cells relatively to single molecules (usual drugs), improving the concentration of the drug and thus its efficiency, which will consequently allow to significantly decrease the side effects. Here we will present the organocatalyzed synthesis and performances of new PMCs of the general formula [RuArLP]+ (Ar=arene, L=heteroaromatic bidentate macroligand and P=coligand), charged with our new emerging ruthenium compounds already recognized as an efficient cancer cell killers. Importantly, our polymers are designed in order to be guided by specific target vectors to efficiently reach the cancer cells. This feature of our new PMCs can also be the key to overcome the toxic side effects of chemotherapy caused by the existing drugs for chemotherapy. The IC50 values in several cancer cell lines, together with a pH dependent hydrolysis in some cases suggest high potentialities for the application of RuPMCs as new drug delivery systems for RuIICp compounds. “Rum oiety”
Polymeric Chain
Targeting Biomolecule
Biography Andreia Valente is graduated in Technological Chemistry from the Faculty of Sciences, University of Lisbon, Portugal. She continued her studies in this institution, where she got her Master degree in Biomedical Inorganic Chemistry. Then, she joined the Unity of Catalysis and Solid State Chemistry at Lille I University, in France, where she obtained her Ph.D. in 2010 in the field of Polymerization Catalysis. Then she joined the Organometallic Group from the Center for Molecular Sciences and Materials at the University of Lisbon where she is now a postdoctoral researcher in the field of polymeric metal complexes for biomedical applications, in cancer therapy.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 60 Pierre Falson et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Unravelling the human multidrug resistance P-glycoprotein poly-specificity Pierre Falson1, Lorena Martinez1, Ophélie Arnaud1, Emilie Henin2, Vincent Chaptal1, RupakDoshi4, HochaoTao3, Michel Tod2, Attilio di Pietro1, Qinghai Zhang3 and Geoffrey Chang4 1CNRS-Lyon 1 University, France 2Ciblage Thérapeutique en Oncologie, France 3The Scripps Research Institute, USA 4School of Medicine University of California, USA
ne main mechanism of drug resistance involves multi-drug efflux pumps which expel drugs out of the cells. How these proteins Opump out hundreds of toxins, and among them anticancer drugs, while displaying marked specificities is mysterious. We bring here a molecular basis of this mechanism of poly-specificity, having localized the H- and R-sites of the human P-gp, two main sites by which drugs efflux occurs, here exemplified with Hoechst 33342 and daunorubicin. We achieved this by characterizing in cellulo inhibition mechanisms of the selenohexapeptide inhibitor QZ59 enantiomers, the first compounds ever co-crystallized with the mouse P-gp(2), combining these data with the structural analysis of the conformations recently reported(3). Results show that the SSS QZ59 enantiomer competitively inhibits Hoechst 33342 and daunorubicin transports, with KI,app of 0.15 and 0.3 µM respectively, 13 and 2 times lower than corresponding Km,app. QZ59-RRR in contrast non-competitively inhibited drugs transport, with a moderate efficacy (KI,app≥1.6 µM) but became competitive towards Hoechst 33342 at high concentrations (KI,app~5 µM). This suggests a positional QZ59 groove drugs transport sites overlap, full for the H-site and partial for the R-site. The latter may share the most embedded QZ59-SSS location as supported by docking analyses. These results will guide the design of compounds acting at the molecular level to block P-gp-mediated drug efflux with the highest efficiency.
Biography Pierre Falson got his Ph.D. at the Lyon University. He is a CNRS Research Director, enzymologist and membrane proteins biochemist, co-leading the ‘Drug resistance mechanism and modulation’ team in the BMSSI CNRS-UCBL1 research unit. He has published 54 publications, patented 6 inventions and licensed to CALIXAR, a startup which he co-founded. He was awarded in 1991 by the Maurice Nicloux prize from the French Society of Biochemistry and Molecular Biology, in 2010 and 2011 by the “National competition of innovative start-ups” and by the Innovation and Transfer Technology prize from the CNRS.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 61 Stefan Deng, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
PK modulation of haptenylated peptides via non-covalent antibody complexation Stefan Deng Roche Diagnostics GmbH, Germany
e applied noncovalent complexes of digoxigenin (Dig) binding antibodies with digoxigeninylated peptide derivatives to Wmodulate their pharmacokinetic properties. A peptide derivative which activates the Y2R receptor was selectively mono- digoxigeninylated by reacting a NHS-Dig derivative with an ε-amino group of lysine 2. This position tolerates modifications without destroying receptor binding and functionality of the peptide. Rationally designed Dig-peptide derivatives can be loaded onto Dig-binding IgGs in a simple and robust reaction, thereby generating peptide-IgG complexes in a defined two to one molar ratio. This indicates that each antibody arm becomes occupied by one haptenylated peptide.In vitro receptor binding and signaling assays showed that Dig-peptides as well as the peptide-antibody complexes retain better potency than the corresponding pegylated peptides. In vivo analyses revealed prolonged serum half-life of antibody-complexed peptides compared to unmodified peptides. Thus, complexes are of sufficient stability for PK modulation. We observed more prolonged weight reduction in a murine DIO model with antibody-complexed peptides compared to unmodified peptides. We conclude that antibody-hapten complexation can be applied to modulate the PK of haptenylated peptides and in consequence improve the therapeutic efficacy of therapeutic peptides.
Biography Stefan Dengl has completed his Ph.D. in 2009 in the laboratory of Prof. Dr. Patrick Cramer at the Genecenter of the Ludwig Maximilians University in Munich. He then joined Roche in Penzberg, Germany, as a postdoctoral fellow working in the field of antibody stability and antibody engineering. Since 2012 he is working as a scientist and expert for biostructure & protein design in pharma research and early development at Roche in Penzberg.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 62 Fazlul Huq, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Tumour active plant derived compounds in combination with targeted therapy towards overcoming drug resistance in ovarian cancer Fazlul Huq The University of Sydney, Australia
hereas platinum resistance is associated with increased expression of anti-apoptotic factors such as NF-kB and AKT, a Wnumber of phytochemicals serve to dampen their expressions so that they may act synergistically in combination. In this study we investigated synergism from combination of platinum drugs and a number of tumour active phytochemicals including curcumin, EGCG, thymoquinone, resveratrol and genistein in human ovarian tumour models. Generally sequenced combinations with 2 to 4 h time gap are found to be synergistic whereas the bolus is often antagonistic. The variation in nature of the combined drug action with change in sequence of administration clearly indicates that the action of one drug modulates that of the other. Proteomic studies have identified over thirty proteins that are believed to be associated with platinum resistance in ovarian cancer. They belong to six major groups including cytoskeletal proteins, molecular chaperone and stress related proteins, proteins involved in detoxification and drug resistance, proteins involved in metabolic processes and mRNA processing proteins. Synergistic outcome from combinations of cisplatin with phytochemicals is found to be associated with down-regulation of mRNA processing proteins that play a variety of roles in tumour development and progression, and up-regulate molecular chaperones that are needed for constant surveillance to ensure normal protein homeostasis. Detoxification and drug resistance proteins are found to be up-regulated after treatment with synergistic combinations of Cis with other phytochemicals, indicating that the phytochemicals have served to sensitize resistant A2780cisR cancer cells towards platinum action by targeting various cellular pathways.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 63 Laila Arzuman, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Designed monofunctional platinums found to have significant antitumor activity Laila Arzuman The University of Sydney, Australia
lthough cisplatin is used in the clinic, its use has also been limited due to the presence of side effects and development of Adrug resistance. Currently much research efforts are being applied in designing new platinums that would interact with DNA differently than cisplatin. In this study, we designed four new platinum(II) complexes of the form [PtL3Cl]Cl coded as LH1, LH2, LH3 and LH4 where L=3-hydroxy pyridine, imidazole, 8-hydroxy quinoline and benzimidazole respectively. Activity of the compounds against human ovarian cancer cell lines: A2780, A2780cisR and A2780ZD0473R, cell uptake, levels of DNA-binding and nature of interaction with pBR322 plasmid DNA have been determined. In addition, combinations of LH1, LH2, LH3 and LH4 with cisplatin and selected phytochemicals were applied to the ovarian cancer cell lines as a function of concentration and sequence of administration. Although LH1 and LH2 are found to be much less active than cisplatin and result into lower intracellular platinum accumulation than cisplatin, LH3 and LH4 are significantly more active than cisplatin especially against the resistant cell lines. Combinations of LH1, LH2 and LH3 with cisplatin are found additive to synergistic against A2780, A2780cisR and A2780ZD0473R cell lines. When combined with phytochemicals genistein and curcumin, LH3 is found to produce sequenced dependent synergism with the bolus showing the greatest synergism. The results of the study can be seen to illustrate structure activity relationships and provides a rational basis for the design of novel platinum-based anticancer drug candidates.
Biography Laila Arzuman is a Ph.D. candidate at the age of 32 years from University of Sydney, Sydney Medical School under the supervision of Professor Fazlul Huq. Her research interest lies in designing new planaramineplatinum(II) compounds for antitumor activity. She received B.Sc. (Honours) in Chemistry (2006) and M.Sc. in Chemistry (2008) from Dhaka University Bangladesh.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 64 Taghreed A. Ibrahim et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
A phytochemical and biological investigation of Aloe grandidentata Salm-Dyck Taghreed A. Ibrahim1, 3, Nabawya M. EL Fiki1, Ibrahim A. Shehata1, 2, Amany A. Sleem4 and Mouchira M. Shoukry1 1Cairo University, Egypt 2King Abd El Aziz University, Saudi Arabia 3King Saud University, Saudi Arabia 4National Research Center, Egypt
he crude leaf extract of Aloe grandidentata was notably anti-inflammatory, chronic antihyperglycemic (100 mg/kg b.wt.) Tand a potent antimicrobial agent compared to standard positive drugs. Phytochemical studies of the leaf extract revealed the isolation and characterization of seven compounds; two new compounds; 1,1',8,8'-tetrahydroxy-3'- acetyl-3-methyl -5,5' bianthracene -9, 9',10,10'-tetraone (2), and 1,6,8-trihydroxy-7-methoxy-3- methyl anthraquinone (3) and five known compounds, β-sitosterol (1), emodin (4), chrysophanol (5), physicon (6) and β-sitosterol-3-O-β-D-glucoside (7). This is the first report of the isolation of emodin from genus Aloe and physicon from family Liliaceae. All structures of the isolated compounds were determined using several spectroscopic techniques; UV, IR, MS, NMR (1H NMR and 13C NMR) and by comparison with literature data.
Biography Taghreed A. Ibrahim has obtained her M.Sc. and Ph.D. degree in Pharmacognosy from Cairo University, Egypt. She is teaching Pharmacognosy and Phytochemistry courses for Bachelor, Pharm.D. and postgraduate students in College of Pharmacy, King Saud University, Riyadh, KSA. Her research interests have been in the broad area of traditional herbal medicine and natural products. She is the director of Quality Unit, College of Pharmacy, King Saud University. She has published more than 25 papers in reputed journals. She is a member and reviewer of several societies and journals and has been serving as an editorial board member of repute journals.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 65 Vaishali M. Patil et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Docking guided QSAR study on a series of N-acetamideindolecarboxylic acid derivatives acting as HCV NS 5B polymerase inhibitors Vaishali M. Patil1, Neeraj Masand2, V. K. Sharma1 and S. P. Gupta3 1Bharat Institute of Technology, India 2Lala Lajpat Rai Memorial Medical College, India 3Meerut Institute of Engineering & Technology, India
ecently, a series of N-acetamideindolecarboxylic acids were studied for their HCV NS5B polymerase inhibition activity. RWe report here a QSAR and docking study on them to investigate the physicochemical and structural properties of the molecules that govern their activity in order to rationalize the structural modification to have more potent drugs. A multiple regression analysis reveals a significant correlation of NS5B inhibition activity of compounds with their hydrophobicity, Kier’s first order valence molecular connectivity index of a substituent and an indicator parameter, suggesting that the hydrophobicity and a particular substituent of the compounds containing atoms with low valence and high saturation will be conducive to the activity. Also the binding of compounds to Site 1 concluded that conformations of HCV NS5B polymerase could be an important regulatory step in RNA synthesis and can be further exploited by designing non-nucleoside inhibitors.
Biography Vaishali M. Patil is an Assistant Professor of pharmaceutical chemistry at Bharat Institute of Technology, Meerut. She has submitted her Ph.D. at Birla Institute of Technology (Mesra), completed B.Pharm from North Maharashtra University and M.Pharm from Uttar Pradesh Technical University. She has some of reviews to her credit in highly esteemed journals, dozens of excellent original research publications in various internationally reputed journals and in addition to it, few chapters in Birkhauser Verlog, Basel published books. Her research interests are computer aided drug design, synthetic chemistry and development of antiviral agents.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 66 Track 5 Day 2 October 16, 2013 5: Drug Discovery Session Chair Session Co-Chair Gerard Rosse Craig M. Williams Dart Neuroscience, USA University of Queensland, Australia
Session Introduction Title: Innovative approaches to expand medicinal chemistry space Gerard Rosse, Dart Neuroscience, USA Title: Discovery of a first-in-class topically bioavailable kit inhibitor with clinical activity using computational chemogenomics technology James Hendrix, nPharmakon LLC, USA Title: Discovery of a small molecule direct keap1-Nrf2 inhibitor as an anti-oxidant inflammation modulator Magesh Sadagopan, Otsuka Maryland Medicinal Laboratories, Inc., USA Title: Can cubane act as a benzene isostere? Craig M. Williams, University of Queensland, Australia Title: Research and development on novel antitumor agents: Preparation, evaluation, and mechanism of low-molecular-weighted phospha sugar derivatives as IER5/Cdc25B targeted antileukemic agents Mitsuji Yamashita, Shizuoka University, Japan Title: Modulators of FGF-FGFR-Heparan sulfate complex: identifications of allosteric antagonists and oligosaccharide agonists as potential novel therapeutics Gilbert Lassalle, Sanofi Aventis, France Title: Chemistry, bioactivity, and computational prediction of binding modes for sarsolenane and capnosane diterpenes as PTP1B inhibitors from the hainan soft coral Sarcophyton trocheliophorum marenzeller Yue-Wei Guo, Shanghai Institute of Materia Medica, China Title: On the field of metallodrugs-new ruthenium compounds as anti-tumor agents Ana Isabel Tomaz, Universidade de Lisboa, Portugal Title: Design, synthesis and antidiabetic, cardiomyopathy studies of cinnamic acid-amino acid hybrid analogs Subir Samanta, Birla Institute of Technology, India Title: Synthesis and screening of newer quinazolin-3(h)-4-0ne derivatives for anticonvulsant activity Jayasekhar P Nair, Oman Medical College, Sultanate of Oman Title: Drug profile matching- drug discovery by polypharmacology-based interaction profiling Zoltan Simon, Eotvos Lorand University, Hungary Title: Novel structural elements for drug discovery: Identification, synthesis and application Pavel Mykhailiuk, Enamine Ltd., Ukraine
MedChem & CADD-2013 Page 67 Gerard Rosse, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Innovative approaches to expand medicinal chemistry space Gerard Rosse Dart Neuroscience, USA
rug discovery proceeds as a multi-stage process, from the identification of a potential therapeutic target through lead Dgeneration, lead optimization, preclinical evaluation to clinical testing, before a new medicine is marketed. Uniting synthetically accessible chemical space with disease relevant biological space represents a significant challenge. Industrial chemical biology approaches have been recognized by pharmaceutical companies as a novel strategy in drug discovery. It encompasses an organizational structure composed of dedicated, specialized teams, thereby enabling a detailed analysis and an optimal use of the chemical and biological space of target classes. The benefits of an industrial chemical biology approaches in combination with automated parallel synthesis and purification will be discussed. A case study for the discovery of novel GPCRs ligands with a focus on the therapeutic areas of inflammation and neurobiology will also be presented.
Biography Gérard Rossé has been involved in drug discovery research and development for more than 15 years. He is currently Associate Director, Structure Guided Chemistry, at Dart Neuroscience and also serves as Adjunct Associate Professor at Drexel University as well as Adjunct Professor in Medicinal Chemistry at the Pennsylvania Drug Discovery Institute. Priorly he functioned in leadership and scientific positions in medicinal chemistry with Cephalon, Sanofi and F. Hoffman-La Roche. During his industrial tenure, he led multidisciplinary teams and invented multiple pre-clinical candidates and compound lead series spanning a wide range of therapeutic indications. These include CNS (cognition, schizophrenia, alzheimer’s disease), inflammation, metabolism, oncology, cardiovascular disease and antibacterial agents. His career is also characterized by implementation of innovative high throughput technology platforms in the area of small molecules and peptides drug discovery, analytical chemistry and data management that increased productivity and accelerated the drug discovery process. He is a distinguished speaker at business meetings in US and Europe and has authored 40+ patents and publications. He received the Ph.D. degree in chemistry from the University of Basel in Switzerland and postdoctoral training at Stanford University.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 68 James Hendrix et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Discovery of a first-in-class topically bioavailable kit inhibitor with clinical activity using computational chemogenomics technology James Hendrix, Dmitri Rebatchouk and Felix Sheinerman nPharmakon LLC, USA
ethods of computational chemogenomics have been used to discover kinase inhibitory activity in a number of clinically safe Mnon-oncology drugs not previously known to inhibit any kinase or to interact with any nucleotide binding proteins. One of these drugs, NPH29, previously in development as a topical dual COX-2/5-LO inhibitor, was found to also inhibit Kit kinase with similar potency. Differing from systemically used Kit inhibitor oncology drugs, NPH29 has low molecular weight (MW<300 Da) and other physiochemical properties suitable for its topical use. Therapeutic relevance of the newly discovered activity of NPH29 against Kit was confirmed in a pilot clinical study - providing the first example of clinical validation of computationally predicted molecular activity leading to new therapeutic indications (“drug retargeting”). The discovery of a topically bioavailable Kit inhibitor NPH29 and rapid clinical confirmation of its activity illustrates the potential of systematic drug retargeting as a productive drug discovery strategy to address new therapeutic targets using existing investigational or approved drugs.
Biography James Hendrix completed his Ph.D. and postdoctoral studies from Colorado State University in organic synthesis. He has over 20 years of experience in drug discovery working for Sanofi-Aventis and predecessor companies where he rose to the level of senior director of CNS Medicinal Chemistry. Currently he is the President of Technology at nPharmakon. He has track record of success in the discovery of drug candidates and lead chemical series. He published more than 30 patents and papers in reputable journals. He is also a member of several scientific advisory boards for both private companies and non-profit foundations.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 69 Magesh Sadagopan, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Discovery of a small molecule direct keap1-Nrf2 inhibitor as an anti-oxidant inflammation modulator Magesh Sadagopan Otsuka Maryland Medicinal Laboratories Inc., USA
eap1-Nrf2-ARE signaling has become an attractive target for the prevention and treatment of oxidative stress-related Kdiseases and conditions including cancer, neurodegenerative, cardiovascular, metabolic and inflammatory diseases. Keap1- Nrf2 protein-protein interaction is considered as a critical point of the pathway that can be targeted for intervention. All currently known Nrf2-activating/ARE-inducing agents function as electrophiles and indirectly inhibit Keap1-Nrf2 interaction through covalent modification of the sensitive cysteine residues of Keap1 or Nrf2. LH601A (ML334), a first-in-class direct inhibitor of Keap1-Nrf2 interaction was identified through HTS of NIH’s MLPCN library using a homogenous fluorescence polarization assay. LH601A is functionally active in both ARE gene reporter assay and Nrf2 nuclear translocation assay, and the binding constant (Kd=1 µM) of LH601A to Keap1 Kelch domain was confirmed using a surface plasmon resonance solution competition assay. The stereospecific nature of binding between LH601A and Keap1, and preliminary structure-activity relationship studies supports that LH601A is a promising lead compound for developing improved and therapeutically applicable derivatives. Biography Magesh Sadagopan is a scientist at Department of Medicinal Chemistry, Otsuka Maryland Medicinal Laboratories. He obtained his B.Pharm degree in 1999 from the Tamilnadu Dr. MGR Medical University, India and his M.S.Pharm in Medicinal Chemistry in 2001 from NIPER (Punjab), India. He obtained his Ph.D. in Bio-organic Chemistry in 2008 from Gifu University in Japan, under the guidance of Prof. KisoMakoto. He held postdoctoral positions at Gifu University (iCeMS, Kyoto University) with Prof. Kiso Makoto and at Rutgers University with Prof. Longqin Hu.
[email protected], [email protected]
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 70 Craig M. Williams et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Can cubane act as a benzene isostere? Craig M. Williams1 and G. Paul Savage2 1School of Chemistry and Molecular Biosciences, University of Queensland, Australia 2CSIRO Materials Science and Engineering, Australia
he synthesis of cubane (1), achieved in 1964 by Eaton, was previously predicted to be impossible, due to the immense strain Tof the molecular structure. Since then a large array of chemical transformations have been performed on the cubane ring system demonstrating the framework to be both a stable and robust building block. Considering the geometry of cubane (1), it is noteworthy that the distance across the cube (the body diagonal) is 2.72 Å, which is almost equivalent to the distance across the benzene ring i.e. 2.79 Å. This similarity is best viewed from one of the 8 apexes (see apex representation 2). Eaton observed that a number of other similarities exist between cubane (1) and benzene (3), for example the enhanced s orbital character of the C-H bond and the similar spatial relationships to ortho and para substituents (i.e. 1,2- and 1,4-disubstitution). However, whilst the physical, or spatial, appearance of cubane (1) is similar to benzene (3), spectroscopically, cubane (1) has both proton and carbon peaks much further up-field in the nuclear magnetic resonance (NMR) spectrum (1H ~4ppm 13C ~50ppm) suggesting obvious electronic differences. This lecture will disclose our recent efforts to explore, using known drugs, whether cubane can act as a benzene ring bioisostere in biologically active molecules.
Biography Craig M. Williams obtained a B.Sc. (Hons) and Ph.D. in synthetic organic chemistry from Flinders University (South Australia) under the supervision of Prof. Rolf Prager. He held an Alexander von Humboldt post-doctorial appointment at the University of Göttingen in Germany (Prof. Armin de Meijere) and an Australian National University post-doctorial fellowship in Canberra (Prof. Lewis N. Mander) before being appointed as a Lecturer in Organic Chemistry at the University of Queensland in 2000. Currently he holds the position of Associate Professor supported by an Australian Research Council Future Fellowship. Williams has published over 90 scientific papers, patents, review articles and book chapters, and supervised 68 researchers to date.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 71 Mitsuji Yamashita et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Research and development on novel antitumor agents: Preparation, evaluation, and mechanism of low-molecular-weighted phospha sugar derivatives as IER5/Cdc25B targeted antileukemic agents Mitsuji Yamashita1, Reiko Makita1, Michio Fujie2, Satoki Nakamura2, Mayumi Yamaoka1, Manabu Yamada1, Junko Yamashita1, Tatsuo Oshikawa3, Kazuhide Asai1, Taishi Niimi1, Takuya Suyama1, Mitsuo Toda1, Yasutaka Tanaka1, Motohiko Kimura1, Haruhiko Sugimura2 and Kazunori Ohnishi2 1Shizuoka University, Japan 2Hamamatsu University School of Medicine, Japan 3Numazu National College of Technology, Japan
ne of the most serious diseases today is cancer which causes the largest number of human death, nevertheless molecular Otargeted drugs are developed and used clinically. In this research novel multiple type molecular targeted antitumor agents of phospha sugar derivatives were investigated. Sugar derivatives, whose oxygen atom in the hemiacetal ring is replaced by a nitrogen atom, etc., are called as pseudo sugars. These pseudo sugars of naturally occurring products such as aza sugars are well investigated to exert bioactivities. One the other hand, phospha sugars which have a phosphorus atom in the hemiacetal ring are not yet so well studied, nevertheless sugar derivatives and organo-phosphorus compounds play important roles in the living being. Apart from the previous methodologies for preparing pseudo sugars based on sugar chemistry, we have prepared various phospha sugars by new methodologies starting from phosphorus heterocyclic compounds, mainly 2- and 3-phospholene derivatives, to construct the library of phospha sugars. Among the phospha sugars prepared branched di- and tri-bromo deoxyphospha sugar derivatives (DBMPP and TBMPP) as well as some substituted phospha sugar analogues were evaluated by MTT in vitro method, and characterized by flow cytometry and western blotting to develop novel low-molecular-weighted antitumor agents. The phospha sugar derivatives enhanced the representation of IER5 and then suppressed the representation of Cdc25B, which is a common factor to accelerate the cell cycle of tumor cells. Therefore, we are expecting that phospha sugars may be developed to be multiple type molecular targeted antitumor agents with wide spectra targeting IER5/Cdc25B.
Biography Mitsuji Yamashita has completed his Ph.D. at the age of 27 years from Nagoya University, Japan, and postdoctoral studies from Toyota Science and Chemistry Research Institute, Japan, and Iowa State University. He was a professor of Graduate School of Science and Technology and retired at the age of 65 years old, and he is now an emeritus professor and specially-appointed professor of Shizuoka University, Japan. His research field is now focused on medicinal materials based on chemistry of carbohydrate and heterocycles. He has published more than 170 papers and patents, as well as contributed four books.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 72 G. Lassalle et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Modulators of FGF-FGFR-heparan sulfate complex: Identifications of allosteric antagonists and oligosaccharide agonists as potential novel therapeutics G. Lassalle1, C. Alcouffe1, C. Herbert1, M. Bianciotto1, P.A. Driguez1, J. Gabriel1, P. Fons1, F. De Smet2, P. Carmeliet2, U. Schieborr3, K. Saxena3, H. Schwalbe3, F.L. Gervasio4, T. Blundell5, J.P. Herault1, J.M. Herbert1 and F. Bono1 1Sanofi Aventis, France 2Vesalius Research Center, Belgium 3University of Frankfurt, Germany 4Spanish National Cancer Research Center (CNIO), Spain 5University of Cambridge, United Kingdom
he fibroblast growth factor (FGF) / fibroblast growth factor receptor (FGFR) signaling network plays an important role in Tcell growth, survival, differentiation and angiogenesis. FGFR activation requires also the presence of heparan sulphate chains functioning as a template to favor dimerization and ultimately signaling during ligand binding. In the search of antagonists of FGFR signaling, we have identified after a lead optimization phase, SSR128129E (SSR), which binds to the extracellular part of the receptor. SSR does not compete with FGF for binding to FGFR but inhibits FGF-induced signaling linked to FGFR internalization in an allosteric manner as shown by crystallographic and NMR studies, Fourier transformed infrared spectroscopy, molecular dynamics simulations, free energy calculations, structure-activity relationship (SAR) analysis and FGFR mutagenesis. SSR is the first reported small molecule allosteric inhibitor of FGF/FGFR signaling, acting via binding to the extracellular part of the FGFR. Conversely, in the search of agonists of these ternary complexes, we have investigated fragments of heparan sulphate. Through rational design, we have identified a series of oligosaccharides optimized in terms of lengths, O-sulfation pattern, N-sulfate optimization and substituents at the reducing end. Apparent incoherent results between biological angiogenic responses and X-Ray structures of ternary complexes, led us to use a panel a biophysical techniques to investigate the dynamics of such complexes leading to a novel reunified model. The potential of these optimized oligosaccharides as therapeutics agents will be discussed.
Biography G. Lassalle has completed his Ph.D. from Rennes University (France) with Dr R.Grée and postdoctoral studies from Ohio State University with Prof. L.A. Paquette. He is the section leader of medicinal chemistry of the “Early to Candidate” (E2C) therapeutic strategic unit (TSU) in Toulouse since 2007, a discovery entity from Sanofi R&D. He is co-author of more than 40 patents and 10 research articles. Moreover, he has contributed to the identification of 2 clinical and 6 preclinical candidates in the cardiovascular/ thrombosis and cancer fields.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 73 Yue-Wei Guo, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Chemistry, bioactivity, and computational prediction of binding modes for sarsolenane and capnosane diterpenes as PTP1B inhibitors from the hainan soft coral Sarcophyton trocheliophorum Marenzeller Yue-Wei Guo Shanghai Institute of Materia Medica, China
hree new sarsolenane diterpenes, dihydrosarsolenone (2), methyl dihydrosarsolenoneate (3), and secodihydrosarsolenone T(4) (exemplified by 2), and two new capnosane diterpenes, sartrochelilides A (6) and B (7) (exemplified by 6), were isolated together with the known analogue sarsolilide A (5), from the Hainan soft coralSarcophyton trocheliophorum marenzeller. Their structures were elucidated by detailed spectroscopic analysis and by comparison with reported data. The absolute configurations of compounds 2 and 6 were determined by TDDFT ECD calculations. In the biotest in vitro, compounds 4-6 exhibited different levels of inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), of which 5 showed the strongest inhibitory activity, being similar to that of positive control oleanolic acid. This is the first report of PTP1B inhibitory activity for sarsolenane and capnosane diterpenes. The discovery promotes computational predictions of binding modes for the enzyme and both kinds of metabolites. OH HO H H H O H O O HO HO O O O O O 2 6 5
Biography Yue-Wei Guo has completed his Ph.D. at the age of 38 years from Naples University and postdoctoral studies from both Istituto di Chimica Biomoleculare-CNR, Italy and Hokaido University, Japan. He is the Professor of Shanghai Institute of Materia Medica-CAS. He has published more than 250 papers in reputed journals and serving as editorial board members of several reputed national/international journals.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 74 Ana Isabel Tomaz et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
On the field of metallodrugs -new ruthenium compounds as anti-tumor agents Ana Isabel Tomaz1, Fernanda Marques2, António P. Matos1, Rodrigo F. M. de Almeida1 and M. Helena Garcia1 1Universidade de Lisboa, Portugal 2Unidade de Ciências Químicas e Radiofarmacêuticas, Portugal
he discovery of the anticancer properties of cisplatin by Rosenberg in the late 60’s paved the way for the development of metal- Tbased cancer therapy. Cisplatin and analogues are to date the only metal-based chemotherapeutics approved worldwide for clinical use. Although highly effective, dose-limiting side effects and the development of resistance to treatment severely limit their clinical value, and ruthenium compounds are a proven effective alternative. We are engaged in the development of ruthenium complexes that combine stability and adequate solubility in aqueous media with a large spectrum of activity against several types of cancer models. In our approach, the problem of the known aqueous instability of monodentate ruthenium complexes is overcome by the use of a bi- or a multidentate ligand. We are currently screening ruthenium-based families exhibiting either piano-stool or octahedral structures for their chemotherapeutic potential. Organometallic {Ru(II)(η5-cyclopentadienyl)} derivatives are examples of the formerwhile Ru(III) complexes with tetradentateaminophenolate ligands are included in the latter. The activity of both ligands and complexes is investigated against human cancer cell lines with a different degree of chemoresistance. We have been working on the mode of action of these prospective metallodrugs, the possibility of drug distribution through the blood by means of serum protein binding (namely human albumin), addressing their cellular uptake and distribution, screening possible cellular targets, cellular morphological alterations and mechanism of cell death. Our compounds typically exhibit moderate to high cytotoxicity in vitro, in some cases largely surpassing that of cisplatin, and are active against cisplatin resistant cell lines. Our findings reveal distinct differences in cellular distribution in comparison to cisplatin and suggest that the major targets for these ruthenium complexes are possibly at the membrane and cytosol rather than the nucleus.
Biography Ana Isabel Tomaz is presently a research assistant in the Organometallic and Bioorganometallic Group of the Center for Molecular Sciences and Materials at the Faculty of Sciences of the University of Lisbon (Portugal) in the field of medicinal inorganic chemistry, where she has been working on ruthenium complexes for cancer treatment. She completed her Ph.D. in 2003 from Instituto Superior Técnico at Technical University of Lisbon on potentially therapeutic vanadium compounds as insulin mimetics in the treatment of diabetes, and continued her postdoctoral studies on the field of metal complexes designed for therapeutic applications at University of Coimbra (Portugal).
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 75 S.Samanta et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Design, synthesis and antidiabetic, cardiomyopathy studies of cinnamic acid-amino acid hybrid analogs S.Samanta, S.Prakash, D. Maji and R.K.Shina Birla Institute of Technology, India
iabetes mellitus, chronic metabolism disorder is characterized by hypergycemia due to insulin deficiency or insulin resistance. DTaking into consideration the high cost of modern treatment we have employed a newer approach of design, synthesis and antidiabetic screening of cinnamic acid and amino acid hybrid compounds. The advent of biotechnology and molecular biology has made the role of peptides and amino acids more significant to influence virtually all body functions. Associated complications include myocardial infarction, cardiomyopathy, retinopathy, neuropathy, and nephropathy. Cinnamic acid analogs (SSPC0-SSPC21) containing different amino acids were designed, docked into crystal structure of AMPK and PPARs. Among the 22 compounds SSPC5, SSPC8, SSPC11, SSPC14, SSPC15 showed good docking scores using Glide 5.0 maestro program and subjected to ADME prediction by using software Quickprop version 3.1. Five best docked compounds were synthesis, characterized and antidiabetic activity carried out using alloxan induced diabetic mice model by measuring blood glucose levels using glucometer at 0, 1, 2, 4, 6, 8 and 24 hrs. SSPC5, SSPC8, SSPC11, SSPC14 showed % reduction of blood glucose of 23.02%, 37.02%, 14.04 and 15.96% as compared to standard glibenclamide with 33.53% reduction. SSPC14 was subjected for the diabetic cardiomyopathy studies by recording the electrocardiogram using Biopac Student Lab PRO System of both diabetic and control rat, analyzed using acknowledge 4 and was found to be very efficient at low dose with a prolong duration of action of the heart (Up to 54 hrs). Thus this study indicated that such hybrid antidiabetic drugs will serve as novel future medicines.
Biography S. Samanta is Professor in the Department of Pharmaceutical Sciences, Birla Institute of Technology, and Mesra, India, with 27 years of teaching and research experience. He is at present guiding 7 Ph.D. students, established the CADD lab for the rational designing and molecular modeling and has been funded by the UCG for UGC-MRP project on antidiabetics. He has 12 international publications to his credit and also received patent for process and product on peptide based antidiabetic compounds.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 76 Jayasekhar P Nair et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Synthesis and screening of newer quinazolin-3(H)-4-one derivatives for anticonvulsant activity Jayasekhar P Nair1 and Mincy Mathew2 1Oman Medical College, Sultnate of Oman 2Medical College, India
uinazolin-4(3H)-one analogues are reported to possess anticonvulsant activity due to non competitive anatagonism of QAMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor). Various Schiff bases of 3-amino-2- phenylquinazolin-4(3H)-one were synthesized after optimizing the molecules for the drug likeness profile and bioactivity index using molinspiration software. The selected candidates were prepared by condensing 3-amino-2-phenylquinazolin-4(3H)- one with different biologically active aryl aldehydes and ketones using microwave irradiation. 2-Phenyl-3-{[(1E)-substituted arylmethylene]amino}quinazolin-4(3H)-one analogous synthesized were characterized by spectral and elemental analysis. The compounds were tested for the preliminary acute toxicity profile before evaluating their anticonvulsant activity using maximal electrical shock (MES) method. Among the compounds synthesizes 3-{[(3E)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]amino}-2- phenylquinazolin-4(3H)-one exhibited significant anticonvulsant activity comparable with that of phenytoin.
Biography Jayasekhar Nair has completed his Ph.D. degree in pharmaceutical chemistry. He is working as Professor of medicinal chemistry and chair of Pharmacy Program of Oman Medical College. He has 25 years of teaching and research experience in medicinal chemistry and has a lot of scientific publications in reputed international journals to his credit. At present he is supervising four Ph.D. candidates and his areas of research interest are molecular modification and pharmacological screening of heterocyclic molecules and computer- aided drug design.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 77 Zoltan Simon et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Drug profile matching- drug discovery by polypharmacology-based interaction profiling Zoltan Simon1,2, Agnes Peragovics1, Balazs Jelinek1,2, Pal Czobor2, Istvan Bitter2, Peter Hari2 and Andras Malnasi-Csizmadia1,2 1Eotvos Lorand University, Hungary 2Drugmotif Ltd., Hungary
ost drugs exert their effects via multi-target interactions, as hypothesized by polypharmacology. Here we introduce drug Mprofile matching (DPM) which is able to relate complex drug-protein interaction profiles with effect and target profiles. Structural data and registered effect profiles of all small-molecule drugs were collected and interactions to a series of non-target protein binding sites of each drug were calculated. Statistical analyses confirmed close relationships between the studied 177 effect and 77 target categories and the in silico generated interaction profiles of cca. 1,200 FDA-approved small-molecule drugs. Receiver operating characteristic analysis and 10-fold cross-validation was performed to assess the accuracy and robustness of the method. Based on the found relationships, the effect and target profiles of drugs can be revealed and hitherto uncovered effects and targets can be predicted in a systematic manner. In order to investigate the predictive power of DPM, three effect categories (angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor and dopamine agent) were selected and predictions in the set of the FDA-approved small-molecule drugs were verified by literature analysis and experimental tests. Moreover, a large set consisting of 600,000 druglike molecules was selected from a database of 50 million compounds and their interaction profiles were generated. Based on these profiles, predictions for the same three effect categories were calculated and tested experimentally.
Biography Zoltan Simon is a biologist who gained his Ph.D. degree in structural biochemistry at Eotvos Lorand University in 2012. His main topic of interest is the application and further perspectives of pattern-based drug design. He is a founding member of Drugmotif Ltd., a Hungarian R&D SME. Besides his scientific interests, he has expertise in research management as coordinator of Hungarian and EU financed research projects. He has 8 publications in international scientific journals and 4 patent applications.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 78 Pavel Mykhailiuk et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Novel structural elements for drug discovery: Identification, synthesis and application Pavel Mykhailiuk Enamine Ltd., Ukraine
t is now commonly accepted that structural diversity of the known drugs is very low. Moreover, it is believed to be one of the Ireasons, why it is getting more and more difficult to launch the principally novel drugs in the recent years. In the contemporary paradigm of drug discovery under the pressure of shortening turnaround time in lead optimization projects, medicinal chemists are to use only commercially available building blocks that can quickly be delivered. Under these circumstances even the most conceptually attractive compounds have low chances to find the true practical application if they are not commercialized. For example, being highly accessible conventional laboratory reagents pyrrolidine, piperidine and morpholine, left their deep footprint in drug discovery. These are the most frequently reported secondary amines in medicinal chemistry. We wanted to upgrade this toolkit of primitive cyclic amines. Therefore, we identified and synthesized other family members allowing for a variety of forms.
Biography Pavel Mykhailiuk completed his Ph.D. in 2008 at Technical University of Karlsruhe (KIT, Germany) after working with Prof. Anne Ulrich. Thereafter, he joined “Enamine LTD” company, where he currently holds a position of Chief Scientific Officer. He is co-author of ca. 50 research manuscripts, 1 patent and 1 book chapter.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 79 Track 12 Day 2 October 16, 2013 12: Recent Research and Developments Session Chair Session Co-Chair John Spencer Carsten Detering University of Sussex, UK BioSolveIT Inc., USA
Session Introduction Title: Synthesis and evaluation of some novel thiazolidinedione derivatives as PPAR-α/γ dual agonist Praveen Thaggikuppe Krishnamurthy, JSS College of Pharmacy, India Title: Unleash the power of the amygdala: How to incorporate MedChem know-how early on in the CADD lead optimization phase Carsten Detering, BioSolveIT Inc., USA Title: Drug discovery: Hit to lead, lead to possible clinical candidates-development of androgen receptor down-regulating agents for the treatment of castration resistant prostate cancer Purushottamachar Puranik, University of Maryland School of Medicine, USA Title: Synthesis of privileged structure libraries for biological evaluation John Spencer, University of Sussex, UK Title: Design, synthesis and pharmacological evaluation of novel hybrid compounds to treat sickle cell disease symptoms Jean Leandro dos Santos, State University of Sao Paulo, Brazil Title: Evaluation of serum levels of cadmium and lead in occupationally exposed painters with administration of probiotic (Lactobacillus pentosus kca 1) supplemented yogurt: A pilot study Osadolor H. B, University of Benin, Nigeria Title: Lipid pattern in serum of patients with type 2 diabetes mellitus Ashur S Eljamil, Tripoli University, Libya Title: What can we expect from new therapeutic strategies in nano-pharmacology and nano-medicine? Hans-Christian Siebert, Research Institute for Bioinformatics and Nanotechnology (RI-B-NT), Germany Title: Mitochondria specific antioxidants and their derivatives in the context of the drug development for neuro degeneration and cancer Gjumrakch Aliev, GALLY International Biomedical Research Consulting LLC., USA
MedChem & CADD-2013 Page 81 Praveen Thaggikuppe Krishnamurthy, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Synthesis and evaluation of some novel thiazolidinedione derivatives as PPAR-α/γ dual agonists Praveen Thaggikuppe Krishnamurthy JSS College of Pharmacy, India
hiazolidinediones (TZDs) or glitazones are an important class of drugs which act by increasing the transactivation activity Tof PPARs, as a result of which, they reduce hepatic glucose production and increase peripheral utilization of glucose and promote lipid metabolism. These actions, therefore, ensure reduced preload and after load on β-cells and lipid homeostasis. In addition, unlike sulfonylureas, these agents are devoid of mechanism based hypoglycemic side effects. There is, therefore, an excellent rationale for the use of TZDs in the management of T2DM. Unfortunately, the clinically used TZDs (troglitazone, pioglitazone and rosiglitazone) suffered with some serious side effects like idiosyncratic hepatotoxicity, fluid retention, weight gain, bladder cancer, etc., as a result of which both troglitazone and rosiglitazone were banned and the pioglitazone label was updated for the risk of bladder cancer.
In recent years, however, new approaches have been made to address the problems associated with current TZDs. One of these is the development of molecules which possess both PPAR-α/γ dual agonistic activities. These molecules have been claimed to achieve a broad spectrum of metabolic effects by improving insulin resistance, hyperglycemia and atherosclerotic dyslipidemia. This presentation talks on the synthesis and evaluation ofin silico and in vitro binding activities of 11 novel (5Z)- 5-[4-(3-phenoxypropoxy)benzylidene]-1,3-thiazolidine-2,4-dione derivatives as PPAR-α/γ dual agents. All the compounds show good binding to both PPAR-α and γ receptors, in the in vitro binding assay. Thein silico studies show diverse possible potential of these molecules to act as agonists and partial agonists/antagonists. These molecules, therefore, may have a potential in the treatment of type 2 diabetes mellitus without the reported adverse effects of the clinically used agents of this class.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 82 Carsten Detering, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Unleash the power of the amygdala: How to incorporate medchem know-how early on in the CADD lead optimization phase Carsten Detering BioSolveIT Inc, Bellevue
iven the amount of pressure under which pharmacompanies have to discover and develop potential drug candidates today, Gone ought to think about how to bring impetus into drug discovery pipelinesthese days: a) shorten the lead optimization cycle. It is more important than ever to quickly advance drug candidates to the clinical phases. b) Venture into unexplored chemical space. Chemical space occupied by existing drugs is increasingly tight, so the urge to get into new chemical classes with unexplored space is of paramount importance. Thus, software enabling the computational and medicinal chemist alike to put their knowledge into the compound design at the same time would render successive project meetings unnecessary. Both researchers would decide right in front of the computer which compounds to make next. The decision can be supported by prioritization, i.e. an estimate of how well the new compound(s) would bind with respect to the reference structure, provided a protein is present. This would provide more confidence in the decision and potentially less time spent synthesizing the wrong molecules. LeadIT is scaffold hopping software that addresses the above mentioned criteria by incorporating years of research with researchers. Its interactive design unleashes MedChem know-how early on in the computational design phase and lets the team come up with tens of variations of the parent compounds in the matter of an afternoon. The talk will highlight the conceptual design of the software with technical aspects as well as a few application scenarios to show-case its capabilities.
Biography Carsten Detering has completed his Ph.D. in Physical Chemistry from Freie Universitaet Berlin, Germany and postdoctoral studies from the University of Washington in Seattle, where he worked on the computational design of a new class of inhibitors for treatment of malaria. He is the CEO of BioSolveIT Inc., the US daughter company of the Germany based BioSolveIT GmbH, the leader in fragment-based, synthesis backed ligand design.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 83 Purushottamachar Puranik, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Drug discovery: Hit to lead, lead to possible clinical candidates-development of androgen receptor down-regulating agents for the treatment of castration resistant prostate cancer Purushottamachar Puranik, Andrew Kwegyir-Afful, David McCarty, Lalji Gediya, Hannah Mbatia and Vincent C.O. Njar University of Maryland School of Medicine, USA
rostate cancer (PC) remains a significant medical burden in the United States. The American cancer society's estimates for PPC in the US for 2013 are: about 238,590 new cases, 29,720 deaths. Suppression of gonadal androgens by medical or surgical castration remains the mainstay of treatment for patients with advanced PC. However, the response to treatment is not durable, and transition to a castration-resistant prostate cancer (CRPC) state is inevitable and incurable. The CRPC cells overexpress functional AR, mutated AR, and most importantly AR isoforms called AR splice variants devoid of the ligand-binding domain. Therefore, current drugs have no effect on AR splice variants implicated in the progression of PC into CRPC. We envision that effective treatment of CRPC patients will require new drugs that can modulate all forms of AR such and AR down-regulating (ARD) agents (ARDAs). For the development of ARDAs, we applied combined analog-based, random screening and medicinal chemistry approaches. Initially, we generated a pharmacophore model for virtual screening and also screened in house compound library. We found VN/124-1 (Phase II clinical candidate) a potent CYP17 inhibitor as hit with mild ARD and anti-androgen activities. Synthetic modification of VN/124-1 resulted into a lead with specific ARD activity (full length and splice variant AR) with no observed secondary activity. Further lead optimization resulted in steroidal and nonsteroidal agents as potential clinical candidates. All approaches and stages involved in the development novel ADRAs will be presented.
Biography Purushottamachar Puranik is currently a Research Associate in Dr. Vincent Njar’s laboratory at University of Maryland Baltimore. He received his Ph. D. degree (2003) from University Institute of Chemical Technology, Mumbai University, India. Thereafter, he worked for Chemical Process Research Laboratory of US Vitamins Ltd., Mumbai, before he join Dr. Vincent Njar laboratory in 2005. He applies computational and synthetic chemistry techniques in discovery and development of prostate and breast cancer agents. He has published more than 25 research articles in reputed journal, and he is editorial board member of Biochemistry and Pharmacology: open access of OMICs publishing group.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 84 John Spencer, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Synthesis of privileged structure libraries for biological evaluation John Spencer University of Sussex, U.K
he synthesis of a diverse drug-like library containing a number of heterocyclic scaffolds is described. Elaborated oxazoles, Tpyridines, pyrimidines, benzodiazepines, benzotriazepines and biphenyls have been synthesized using a combination of microwave-assisted organic synthesis (MAOS), supported reagents and automatic chromatography. These have been screened against a number of biological targets. Focused libraries have been designed against a number of cancer-relevant targets, namely urokinase, histone deacetylases (HDACs) and p53. Rationalization of these hits has been achieved via molecular modeling and X-ray cocrystallisation studies.
Biography John Spencer holds a Ph.D. from Strasbourg University and carried out postdoctoral research at the ETH, Zurich. He is a reader at Sussex, with ten years’ industrial leadership in medicinal chemistry. He is an author of over 80 publications and inventor on 10 patents. His interests are in parallel synthesis, microwave chemistry, catalysis, boron chemistry and fragment based drug discovery.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 85 Jean Leandro dos Santos, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Design, synthesis and pharmacological evaluation of novel hybrid compounds to treat sickle cell disease symptoms Jean Leandro dos Santos State University of São Paulo (UNESP), Brazil
ickle cell disease (SCD) is one of the most prevalent hematological disorders that affect several persons worldwide. The disease Sis characterized by a punctual mutation at sixth codon of the β-globin gene (GTG to GAG) that modified the translation of glutamic acid (Glu6) to valine (Val6). Hydrophobic interactions induce hemoglobin polymers at low oxygen state that change the structure of erythrocyte into rigid irregularly shaped cells. The abnormal adhesion of cells to endothelium contributes to develop vaso-occlusive process. Nowadays the only drug approved by FDA to treat SCD symptoms is the antineoplasic hydroxyurea which demonstrated several adverse effects during long-term therapy. Several targets have been explored to discovery new drugs to treat SCD symptoms, as for example, the inflammation and fetal hemoglobin production. We have been design, synthesized and evaluated a series of hybrid compounds targeting multiple pathways such as decrease pro-inflammatory cytokines and ability to induce gamma-globin gene expression. All compounds demonstrated to be more active and less mutagenic than hydroxyurea. These compounds have emerged as new leading drug candidate with multiple beneficial effects for the treatment of sickle cell disease symptoms and provide an alternative to hydroxyurea treatment.
Biography Jean Leandro dos Santos has completed his Ph.D. at the age of 25 years from School of Pharmaceutical Science at State University of São Paulo (UNESP). He has published more than 30 papers in reputed international journals, 12 patents and serving as an editorial board member of some journals. The professor has several published resumes in different conferences worldwide. He has worked in collaboration with national and international pharmaceutical industries aiming to discover new compounds to treat sickle cell disease, infections and inflammatory diseases. He has performed supervision of several postgraduate students.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 86 Osadolor H. B et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Evaluation of serum levels of cadmium and lead in occupationally exposed painters with administration of probiotic (Lactobacillus pentosus kca 1) supplemented yogurt: A pilot study Osadolor H. B, Igharo O. G, Okuo R. O and Anukam K. C University of Benin, Nigeria
admium and lead are extremely toxic metals found in industrial workplaces. They are also found in some industrial paints Cand may represent hazards when sprayed. It interferes with the development of the nervous system and particularly toxic to children. Occupational exposure is a common cause of cadmium and lead poisoning in adults. Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. Probiotics are commonly consumed as part of fermented foods with specially added active live cultures; such as in yogurt. Lactobacillius pentosus KCA1 used in this study is recently discovered and sequenced lactobacilli of probiotic strain with a potential for detoxification of heavy metals. Serum levels of lead and cadmium were determined in thirty professional painters and ten non painters as control using atomic absorption spectrophotometer (AAS Model SOLAAR 969 UNICAM series). Probiotic supplemented yogurt was administered to the occupationally exposed painters and its effect on serum levels on cadmium and lead were also determined. The results obtained show that mean ± standard error of mean (S.E.M.) of serum levels of cadmium (0.012±0.01ppm/L) and lead (0.025±0.003ppm/L) were higher in painters and significantly different compared with values obtained in non painters (controls); (0.005±0.002 ppm/L) and (0.02±0.01 ppm/L) for cadmium and lead respectively; (p<0.05). Mean serum level of Lead in the painters after administration of probiotic supplemented yogurt (0.008±0.002 ppm/L) was significantly reduced compared with levels before administration of the yogurt (0.025±0.003ppm/l); (p<0.001). From this study, serum level of cadmium and lead were reduced in occupationally exposed painters by probiotics (Lactobacillus pentosus KCA1) which was prepared in form of yogurt. Comparatively, serum lead levels were more significantly reduced than cadmium levels in the occupationally exposed painters.
Biography Osadolor, H.B. has completed his Ph.D. at the age of 40 years from University of Benin. He is a senior lecturer and currently Head of Department of Medical Laboratory Science, University of Benin, Nigeria. He has over 30 papers in reputed journals including PubMed.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 87 Ashur S et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Lipid pattern in serum of patients with type 2 diabetes mellitus Ashur S, Eljamil1, Khaled Ammar Elnakaa2, Salma Elmaradi2 1Tripoli University, Libya 2Tripoli Medical Centre, Libya
he most common pattern of diabetic dyslipidemia is elevated triglycerides levels and decreased high density lipoprotein Tcholesterol (HDL-C) levels. Type 2 diabetic patients may have elevated levels of non-high density lipoprotein cholesterol (non-HDL-C). The concentration of low density lipoproteins cholesterol (LDL-C) was reported to be not significantly different from non-diabetic individuals. Recently it has been reported that the measurement of LDL-C as well as triglycerides may not be fully standardized in many clinical laboratories. The present study is designed to compare the serum lipid pattern of type 2 diabetes mellitus patients with non-diabetic individuals and the LDL-C was determined by a direct method. Fasting blood samples were collected from 94 subjects (47 diabetic and 47 non-diabetic). In the present study diabetic samples showed, significantly higher levels of total cholesterol, TC (175.34 mg/dl±30.7), LDL-C (112.68 mg/dl±27.9), non-HDL-C (136.06 mg/dl±28.9) and TG (144.04 mg/dl±55.7), than non-diabetic samples, TC (150.26 mg/dl±24.7), LDL-C (90.74 mg/dl±22.1), non-HDL-C (104.54 mg/dl±24.2) and TG (97.6 mg/dl±33.8), with p values of p<0.0004, p<0.0001, p<0.00001, p<0.00001, respectively. Diabetic serum samples showed significantly lower HDL-C levels, (39.53 mg/dl±9.2) than that of non-diabetic samples, (43.94 mg/dl±9.8), with p value of p<0.03. Conclusion: Diabetic patients had a high TC, TG, LDL-C and non-HDL-C levels than the non-diabetic individuals, which may indicate that diabetic patients are more susceptible to cardiovascular disease than the non-diabetic individuals.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 88 Hans-Christian Siebert, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
What can we expect from new therapeutic strategies in nano-pharmacology and nano- medicine? Hans-Christian Siebert Research Institute for Bioinformatics and Nanotechnology (RI-B-NT), Germany
hen talking about nano-pharmacology and nano-medicine one can expect fundamental new solutions in the broad fields Wof pharmacy as well as human and veterinary medicine. However, it is not only the precise knowledge about the molecular interactions on a nanoscale level. Furthermore, it is essential to understand and apply the sub-molecular based survival strategies which e.g. marine organisms are using for more than a billion years. The arsenal of methods used in the Research Institute for Bioinformatics and Nanotechnology (RI-B-NT) for the functional and structural elucidation of bioactive molecules is applied on various molecules from plant and animal origin. Beside clinical studies and cell biological techniques, NMR, molecular modeling (especially quantum chemical calculations), mass spectrometry, atom force microscopy, surface plasmon resonance techniques and also measurement with a quartz crystal microbalance are carried out. This combination of methods is extremely suited for the analysis of various processes in the extracellular matrix, which are related to nerve cell repair, antimicrobial processes and cancer therapy. One main research project of our institute concerns bio-active molecules in Cnidaria (e.g. jellyfishes). Jellyfishes are a rich source of interesting collagen variants, lectins, defensins and proteoglycans. We are testing these molecules after detailed structural analysis in various cell cultures as well as in clinical studies.
Biography Hans-Christian Siebert has a Diploma in Physics, is a Doctor of Rerum Naturalium, Doctor of Vetenary Medicine and is a Professor of Biochemistry and Biophysics at the Universities of Kiel and Heidelberg. He has done dissertation at the Max-Planck-Institute for Medical Research, Heidelberg. He did his post doc at the University of Utrecht (NL), Bijvoet Center for Biomolecular Research at the Departments of Bioorganic Chemistry and NMR-Spectroscopy. Habilitation (Venia legendi for Biochemistry), Ludwig-Maximilians-University, Munich. Since 2007: he is serving as chair of Biochemistry and head of the institute for Biochemistry and Endocrinology, Faculty for Veterinary Medicine, Justus-Liebig-University Giessen. Since 2010 he is the scientific director at the Research Institute for Bioinformatics and Nanotechnology (RI-B-NT) at the KITZ in Kiel, Germany.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 89 Gjumrakch Aliev, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Mitochondria specific antioxidants and their derivatives in the context of the drug development for neuro degeneration and cancer Gjumrakch Aliev GALLY International Biomedical Research Consulting LLC, USA
xidative stress induced mitochondrial DNA overproliferation and/or deletion of the organ and/or tissues, especially Othe mitochondrial energy demands, have been implicated in the pathogenesis of several diseases, including AD, tumor growth, and metastasis. The present study has determined if an intimate, i.e. causal, relationship between oxidative stress and mitochondrial damage and/or vascular lesions occurs before the development of human AD, in animal models that mimic human neurodegeneration and human colorectal carcinoid cancer or malignant brain cancer. In situ hybridization and ultrastructural analysis of the mitochondria (mitochondria with electron dense matrix, mitochondrial-derived lysosomes) showed that mitochondria with the abnormal structures and lipofuscin appear to be features of hippocampal damaged neurons in human AD, aged Tg (+) mice, 2 vessel occlusion model of the brain hypoperfusion, and malignant primary and metastatic cancer. The abnormal mitochondria appeared to be a permanent feature in all cellular compartments; in situ hybridization analysis with mouse and human mtDNA probes found a large amount of deleted mtDNA in human AD and in all models that mimic human AD hippocampus and cancer tissues compared to aged controls. Our study, for the first time, demonstrated the pattern of oxidative stress induced mitochondrial DNA overproliferation and/or deletion during the development of human AD, and animals that mimic human AD, colorectal cancer in liver metastasis, and malignant brain cancers, which can be used as new diagnostic tools and/or criteria for the earlier detection, and future considerations new and more specific and effective treatment strategies against for these devastating diseases.
Biography Gjumrakch Aliev, completed his MD and Ph.D. at the age of 27 years from Moscow State University, Russia and postdoctoral studies from University College London. He is the president & CEO of GALLY International Biomedical Research Consulting LLC, a world class premier biomedical service organization. He has published more than 180 papers in reputed journals and serving as an editors' chief and editorial board member of more than 80 nationally and internationally reputed journals.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 90 Track 10 Day 3 October 17, 2013 10: Receptors and Inhibitors Session Chair Session Co-Chair Prabagaran Narayanasamy Xiang-Qun (Sean) Xie University of Nebraska Medical Center, USA University of Pittsburgh, USA
Session Introduction Title: The Hsp90 C-terminal binding site, instructions for and ramifications of inhibition Brian S. J. Blagg, The University of Kansas, USA Title: Inhibition of prostanoid receptor EP2: A novel anti-inflammatory therapy for chronic neurodegenerative and autoimmune diseases Thota Ganesh, Emory University School of Medicine, USA
Title: Selective vitamin K2 biosynthesis inhibitors to treat non-replicating Mycobacterium tuberculosis Michio Kurosu, University of Tennessee Health Science Center, USA Title: Inhibitors of fatty acid amide hydrolase (FAAH): SAR and results in pre-clinical pain models J. Guy Breitenbucher, Dart Neuroscience LLC, USA Title: Discovery of novel bicyclic derivatives to stop the growth of Mycobacterium tuberculosis by inhibiting MenA Prabagaran Narayanasamy, University of Nebraska Medical Center, USA Title: The synthesis of potential inhibitors of panthothenate synthetase Kellie L. Tuck, Monash University, Australia Title: Design and synthesis of inhibitors of cysteine protease Debatosh Majumdar, Glycosyn LLC, USA Title: Inward rectifier potassium channels as emerging drug targets Jerod S. Denton, Vanderbilt University School of Medicine, USA Title: Identification of a new class of SUMO specific protease 2 inhibitors utilizing structure based virtual screening approach Ashutosh Kumar, Zhang Initiative Research Unit, RIKEN, Japan Title: Are D-neurons and trace amine-associated receptor, Type 1 involved in mesolimbic dopamine hyperactivity of schizophrenia? Keiko Ikemoto, Fukushima Medical University, Japan Title: Harnessing human N-type Ca2+ channel receptor by identifying the atomic hotspot regions for its blocker design C. Gopi Mohan, Amrita Vishwa Vidyapeetham University, India Title: Discovery of small molecule inhibitors of protein-protein interactions using DNA-encoded chemical libraries Nils Jakob Vest Hansen, Vipergen ApS, Denmark Title: Post-marketing surveillance of active pharmaceutical ingredients in antimalarial drugs used in Malawi Ibrahim Chikowe, University of Ghana, Ghana
MedChem & CADD-2013 Page 91 Brian S. J. Blagg, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
The Hsp90 C-terminal binding site, instructions for and ramifications of inhibition Brian S. J. Blagg The University of Kansas, USA
sp90 is a molecular chaperone that is responsible for the conformational maturation of more than 200 known substrates, Hmany of which are associated with signaling pathways that are hijacked by transformed cells. As a result, Hsp90 has evolved into a promising anti-cancer target as multiple signaling nodes can be targeted simultaneously through Hsp90 inhibition. More than 15 small molecules that bind to the Hsp90 N-terminal binding pocket have entered clinical trials for evaluation against a number of human malignancies, but unfortunately, a lack of efficacy and/or toxicity has been observed for many of these candidates. In an effort to develop new strategies toward Hsp90 inhibition, we have focused on inhibition of the C-terminal binding site. These methods have resulted in molecules that can segregate induction of the pro-survival heat shock response from client protein inhibition/degradation, and consequently have afforded new methods for the potential treatment of protein misfolding diseases and cancer, respectively. This presentation will provide an overview of the Hsp90 C-terminal binding site and the development of inhibitors that can treat cancer or neurodegenerative diseases.
Biography Brian S. J. Blagg completed his Ph.D from the University of Utah in 1999,followed by a postdoctoral position at The Scripps Research Institute. He is currently a Professor of medicinal chemistry at The University of Kansas and serves on several Editorial Advisory Boards for Medicinal Chemistry Journals and is an Associate Editor for the Journal of Medicinal Chemistry. The Blagg research Group has won several awards, including the 2009 American Chemical Society’s David W. Robertson Award for excellence in Medicinal Chemistry.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 92 Thota Ganesh, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Inhibition of prostanoid receptor EP2: A novel anti-inflammatory therapy for chronic neurodegenerative and autoimmune diseases Thota Ganesh Emory University School of Medicine, USA
nflammation is a key driver of many chronic central nervous system and peripheral diseases. While COX-2 inhibitors proved to Ibe efficacious in reducing the pain and severity of the disease in patients with arthritis, they have not provided any benefit to the patients with neurodegenerative diseases such as Alzheimer’s and epilepsy. Recently two clinically used COX-2 drugs, Vioxx® and Bextra®, have been withdrawn from the United States market due to cardiovascular side effects, raising the limitation on future use of the COX-2 inhibitors. Studies have confirmed that the side effects by the COX-2 drugs are due to blocking of the prostanoid receptor IP, downstream of COX-2 enzyme. The IP receptor functions as a cardioprotective agent and prevents hypertension, stoke and atherosclerosis. Thus future anti-inflammatory therapy should be mediated through a specific pro-inflammatory prostanoid receptor. The EP2 receptor is emerging as a pro-inflammatory target in variety of chronic neurodegenerative and peripheral disease models. We have recently identified a novel class of EP2 antagonists and by medicinal chemistry we have developed a lead compound with requisite plasma and brain pharmacokinetics. We also demonstrated that this compound is able to blunt the inflammation and neurodegeneration in a mouse model of status epilepticus (epilepsy). This lecture will provide an overview on EP2 antagonism as an alternative anti-inflammatory approach in comparison to COX-2 inhibition.
Biography Thota Ganesh completed his Ph.D. from Osmania University, India in 1999, then he did postdoctoral work at University of Durham, UK, and then in laboratory of David G. I. Kingston at Virginia Tech. He joined Emory Chemical Biology Discovery Center as senior scientist, and he was recently promoted to an Assistant Professor at the Department of Pharmacology, Emory University. He has published more than 40 publications in peer- reviewed journals and 8-patents. His recent contributions include evaluation of bioactive conformation of anti-cancer agents Taxol and epothiolones, development of small molecule inhibitors for Hsp90, histone methyltransferases, NADPH-oxidases (NOX) and EP2 receptor.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 93 Michio Kurosu, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Selective vitamin K2 biosynthesis inhibitors to treat non-replicating Mycobacterium tuberculosis Michio Kurosu University of Tennessee Health Science Center,Memphis, USA
he emergence of multidrug-resistant strains of M. tuberculosis (Mtb) seriously threatens TB control and prevention efforts. TIn general TB chemotherapy, a combination of four TB drugs isgiven for at least six to nine months for drug-susceptible Mtb infections. Thus, it is considerably important to discover promising approaches to shorten a TB drug regimen.Mechanisms that enter non-replicating state of Mtb are accounted for a significant factor that requires long-term chemotherapy. Therefore, new drugs that target non-replicating Mtb are likely to revolutionize TB chemotherapy. Majority of Gram-positive bacteria including
Mycobacterium spp. utilize only menaquinone (vitamin K2) in their electron transport systems, and menaquinone biosynthesis is essential for survival of Gram-positive bacteria. On the other hand, Gram-negative organisms utilize ubiquinone (CoQ) under aerobic conditions, and menaquinone under anaerobic conditions.Thus, inhibitors of menaquinone biosynthesis systems have great potential for the development of novel and selective drugs against MDR Gram-positive pathogens. We have discovered optically active MenA (the 6th enzyme in menaquinone biosynthesis) inhibitors that showed significant growth inhibitory activity µ against non-replicating Mtb (MICLORA, 0.85 g/mL) with the MICLORA/MICMABA value of 0.37. The discovery of molecules that
kill non-replicating Mtb at lower MIC (MICLORA) than the MIC obtained under aerobic conditions (MICMABA) is expected to be of significance in terms of discovering new lead molecules that can be developed into new drugs to kill Mtb in any states. This presentation will illustrate the assay protocol for identification of selective MenA inhibitors, and novel antimycobacterial MenA inhibitors that killed non-replicating Mtb at low concentrations.
Biography Michio Kurosu received his Ph.D. from Osaka University (Japan), School of Pharmaceutical Sciences and broadened postdoctoral training and experience at Harvard University, Department of Chemistry and Chemical Biology. He is an Associate Professor at University of Tennessee Health Science Center. He has published more than 85 papers in reputed journals and has been serving as NIH study section reviewers. He has a long-term interest in development of new antibacterial agents targeting novel drug targets.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 94 J. Guy Breitenbucher, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Inhibitors of fatty acid amide hydrolase (FAAH): SAR and results in pre-clinical pain models J. Guy Breitenbucher Dart Neuroscience LLC, USA
harmacologically active preparations of Cannabis sativa have been recognized since ancient times as having potentially useful Ptherapeutic effects, including analgesia. With the discovery and cloning of the cannabinoid receptors CB1 and CB2, and the subsequent discovery of anandamide, the first endogenous substance with agonist activity at both receptors, a rationale for the analgesic effects of cannabis was developed. Anandamide has a short half-life, due to rapid hydrolysis by the enzyme fatty acid amide hydrolase (FAAH) resulting in low resting concentrations in the CNS. FAAH knockout mice have been described and have elevated resting brain concentrations of anandamide, and manifest a phenotypic analgesia in several commonly used models of pain. Furthermore, known inhibitors of FAAH show amelioration of pain behaviors in rats. The present account describes the discovery of a novel classes of FAAH inhibitors and describes our work to characterize the SAR and pharmacology of these FAAH inhibitors.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 95 Prabagaran Narayanasamy, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Discovery of novel bicyclic derivatives to stop the growth of Mycobacterium tuberculosis by inhibiting MenA Prabagaran Narayanasamy University of Nebraska Medical Center, USA
uberculosis (TB) is the second largest infection in number of deathsaround the world. Importantly, about one third of Tworld population has latent tuberculosis. However, HIV-TB is growing fast, especially HIV is stimulating latent TB to form active TB infection. In addition drug resistant TB is also a challenge for researchers. In this order novel drugs are necessary to eradicate TB. Most of the TB drugs were based on inhibiting the process of cell wall and protein synthesis, therefore a novel method is important for drug discovery and development.Interestingly, Bacilli require electron transport chain components and ATP synthesis for survival. The lipoquinones involved in the respiratory chains of bacteria consists of menaquinones and ubiquinones where else; mammals require only ubiquinone, which makes more specific to Bacilli. In relation, menaquinone is an essential component in theelectron transfer process, similarly, MenA is an essential enzyme involved in the synthesis of menaquinone. In addition menaquinones are the major lipoquinones of mycobacteria and other Gram Positive bacteria. Hence MenA promising drug target is explored in determining the inhibitor. While screening and designing inhibitors we observed that bicyclic derivatives showed high coordinating complexes with enzymes in transition state and interrupted the growth of M. Tb. Especially, alkylamino bicyclic complexes showed extensive inhibition towards Mtb. The quantitative structure activity relationship was carried out for the alkyl amino bicyclic complex and tested against Gram Positive bacteria. After optimizing the inhibitorswe observed promising MIC and IC50 values to encounter the infection.
Biography Prabagaran Narayanasamy is a faculty member in the Department of Pharmacology and Experimental Neurosciences at the University of Nebraska Medical Center. He received his Ph.D. at IIT in Organic Chemistry and did his postdoctoral studies at North Dakota State University, Harvard University and University of Illinois Urbana-Champaign. Later, he joined as a Research Scientist at Colorado State University to explore drug discovery. He has been a faculty at University of Nebraska Medical Center since 2012. His research interests are on development, delivering and discovering drug for anti-mycobacterial medicine and antiretroviral therapy. Conventional drugs and new inhibitors are used in nanoformulation to generate active nanomedicine. For antibacterial drug discovery glyoxalase, quorum sensing, MEP and menaquinone pathway are utilized. Additionally, development of exosomes as drug delivering agent is initiated for infectious disease. In addition, metabolites are evaluated in the infected brain for characterizing neurodegenerative disorders.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 96 Kellie L. Tuck, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
The synthesis of potential inhibitors of panthothenate synthetase Kellie L. Tuck Monash University School of Chemistry, Clayton, Australia
antothenate synthetase is the last enzyme in the pantothenate pathway (Fig.1). Pantothenate is biosynthesised in micro- Porganisms, plants, and fungi, but not in animals, consequently inhibiting pantothenate biosynthesis could offer new drug targets to combat virulent pathogens, for example Mycobacterium tuberculosis. Pantothenate synthetase catalyses the ATP- dependent condensation of pantoate and β-alanine, resulting in the formation of pantothenate. It is known that acylsulfamoyl adenosines mimic the pantoyl adenylate intermediate formed during the enzymatic reaction and consequently are potent to good inhibitors. We have been investigating the role of how variation of the pantoate moiety influences the inhibition of the acylsulfamoyl analogues. Consequently, we have synthesized and tested a series of acylsulfamoyl adenosines in order to explore the role of the pantoate moiety. This talk will describe the synthesis of a range of compounds and their inhibition of pantothenate synthetase.
keto antoate OH O O p KPHMT reductase CO H CO2H anB 2 CO2H p panE H OH a α-isoketovalerate O
HO C β-alanine pantothenate 2 synthetase NH2 panC aspartate panD decarboxylase OH H N H CO2H CO2 HO2C O OH NH2 pantothenate
Figure 1: The biosynthesis of pantothenate (Vitamin B5) in bacteria, yeast and plants.
Biography Kellie L. Tuck completed her Ph.D. studies in 1999 at the age of 24 from the University of Adelaide, Australia. Following this, she worked as a post- doctoral research fellow, at the School of Pharmacy, University of South Australia and University Chemical Laboratories, University of Cambridge. She took up a teaching and research position at Monash University in late 2004. Her research focus is of an interdisciplinary nature and is interested in applying organic chemistry to solve fundamental problems. The results of her research have been published in a total of 43 refereed journal papers.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 97 Debatosh Majumdar, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Design and synthesis of inhibitors of cysteine protease γ-glutamyl hydrolase Debatosh Majumdar Glycosyn LLC, Medford, USA
olic acid and its derivatives are important for metabolic processes crucial to human health. Intracellular polyglutamylation Fof folates and antifolates is performed in a reaction catalyzed by an ATP-dependent enzyme folylpolyglutamate synthetase (FPGS, EC 6.3.2.17), whereas the reverse process, hydrolysis of folylpolyglutamates to monoglutamyl derivatives occurs in a reaction catalyzed by a cysteine protease, γ-glutamyl hydrolase (GH, EC 3.4.22.17). GH is a lysosomal and secreted glycoprotein that is very selective for γ-glutamyl peptide bonds. GH is overexpressed in cancerous hepatic and breast tissue. Tumor cells having high levels of GH are inherently resistant to classical antifolates. Proper function of γ-glutamyl hydrolase is very important for the homeostasis of folylpolyglutamate and antifolate pharmacology. The mechanism of GH-catalyzed amide bond hydrolysis is similar to that of the cysteine protease, papain. Earlier it was shown that the natural peptidyl epoxide E-64 can function as an inhibitor for cysteine proteases, e.g., cathepsin, papain, ficin, etc. In an effort to understand the detailed function of GH, we have synthesized novel internal γ-glutamyl peptidyl epoxides, 1 and 2, as inhibitors for GH (Figure 1). In these molecules, the scissile amide bonds have been replaced by an internal epoxide functionality so that they will be devoid of substrate type activity. At the same time, the epoxide functionality will act as an electrophile in the active site which, in the presence of a general acid, will allow nucleophilic attack by the cysteine thiol on the epoxide functionality thus leading to irreversible inhibition of GH.
H O H O O CO2H O O CO2H O OH OH
N CO H N CO2H H H 2 H H MeHN MeHN 1 2
Biography Debatosh Majumdar has completed his Ph.D. from the Complex Carbohydrate Research Center at the University of Georgia. He worked on the design and synthesis of biologically important carbohydrates and glycopeptides. He was a research fellow at the University of Michigan Ann Arbor, where he worked on the design and synthesis of cysteine protease inhibitors. Then he worked on cancer therapy and cancer nanomedicine at Emory Winship Cancer Institute. Now, Debatosh is a scientist at Glycosyn LLC, a premier biopharmaceutical company. He has published many papers and book chapters, and has been serving as an editorial board member of the World Journal of Organic Chemistry, and reviewers of Frontiers in Bioscience.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 98 Jerod S. Denton, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Inward rectifier potassium channels as emerging drug targets Jerod S. Denton Vanderbilt University School of Medicine, USA
n emerging body of genetic and physiological evidence suggests that certain members of the inward rectifier potassium A(Kir) channel family represent novel drug targets for several common diseases. With few exceptions, however, the molecular pharmacology of the family has remained essentially undeveloped since the first member was cloned more than two decades ago. The Renal Outer Medullary K+ channel (ROMK), or Kir1.1, plays pivotal roles in the regulation of fluid-volume and electrolyte homeostasis by the kidney. Heritable loss-of-function (LOF) mutations in ROMK in patients with Type 2 Bartter syndrome lead to renal salt wasting and lower blood pressure. Similarly, LOF mutations in the gene encoding Kir4.1 lead to SeSAME/EAST syndrome, a complex disorder presenting with renal salt-wasting, low blood pressure, and neurological deficits. High-throughput screening of the NIH Molecular Libraries Small-Molecule Repository, medicinal chemistry, electrophysiology, and molecular modeling are being used to develop tool compounds for interrogating the therapeutic potential of Kir1.1 and Kir4.1 as novel diuretic targets. Progress toward developing inhibitors of mosquito Kir channels for use as insecticides to limit the transmission of malaria and other debilitating vector-borne diseases will also be discussed.
Biography Jerod S. Denton earned his Ph.D. in integrative physiology from Dartmouth College in 2002 and went on to do postdoctoral training with Kevin Strange at Vanderbilt University. He joined the faculty in the Departments of Anesthesiology and Pharmacology at Vanderbilt in 2005, where his lab has focused on developing the molecular pharmacology for the inward rectifier potassium channel family. His lab has been funded by grants from the American Heart Association, National Kidney Foundation, the NIH and Foundation for the NIH.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 99 Ashutosh Kumar et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Identification of a new class of sumo specific protease 2 inhibitors utilizing structure based virtual screening approach Ashutosh Kumar, Akihiro Ito, Misao Yoneyama, Minoru Yoshida and Kam Y. J. Zhang RIKEN, Japan
UMO specific proteases (SENPs) are cysteine proteases that carry out the proteolytic processing of SUMO from its pro form Sas well as its deconjugation from substrate proteins. SENPs are attractive targets for drug discovery due to their crucial role in development of various diseases. However, until now the SENPs inhibitor discovery efforts were focused toward SENP1 and only a few inhibitors or activity based probes have been identified for SENP2. Moreover, none of the reported chemical class is selective for SENP2. In these circumstances, to study therapeutic and biological roles of SENP2 in various diseases, it is desirable to identify selective inhibitors with new chemical scaffold. Here in this study, we used the combination of structure based virtual screening and quantitative FRET based assay to identify several inhibitors of SENP2. Our virtual screening protocol initially involves the identification of small molecules that have similar shape and electrostatic properties with the conjugate of SUMO1 C-terminal residues and substrate lysine. Molecular docking was then used to prioritize the compounds for biological assay. Out of 49 compounds that were acquired and tested for SENP2 inhibitory activity, eight compounds displayed IC50 in low to moderate μM range. Five of these compounds belong to 1, 2, 5-oxadiazoles that represent novel class of small molecules selectively inhibiting SENP2. With a goal to improve the inhibitory potency and explore structure activity relationship of 1, 2, 5-oxadiazoles, structurally related compounds were identified. The biological assay results confirms SENP2 inhibitory activity and selectivity of 1, 2, 5-oxadiazoles. Our study suggests that 1, 2, 5-oxadiazoles could be used as a starting point for the development of novel therapeutic agents against various diseases targeting SENP2.
Biography Ashutosh Kumar has completed his Ph.D. from Central Drug Research Institute, India and currently working as postdoctoral research fellow in Zhang Initiative Research Unit, RIKEN, Japan. His current research interest lie mainly in the field of cancer drug discovery utilizing structure-based drug design approaches. He has published several research papers in peer reviewed journals.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 100 Keiko Ikemoto, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Are d-neurons and trace amine-associated receptor, type 1 involved in mesolimbic dopamine hyperactivity of schizophrenia? Keiko Ikemoto School of Medicine, Fukushima Medical University, Japan Iwaki Kyoritsu General Hospital, Japan Shiga University of Medical Science, Japan
lthough dopamine (DA) dysfunction is a well-known hypothesis for etiology of schizophrenia, molecular basis of mesolimbic ADA hyperactivity has not yet been clarified. To explain this, modulating function of trace amines on DA neurotransmission and the decreased number of striatal D-neurons, trace amine-producing neurons were newly considered. Notably, trace amine- associated receptor, type 1 (TAAR1), a subtype of trace amine receptors, has a large number of ligands, including tyramine, β-phenylethylamine and methamphetamine, which influence on human mental state and is now regarded as a target receptor for novel neuroleptics. Reduced stimulation of TAAR1 on DA neurons in the midbrain ventral tegmental area (VTA) has been revealed to increase firing frequency of VTA DA neurons. The author and her colleagues reported the decrease of D-neurons in the striatum and nucleus accumbens of postmortem brains of patients with schizophrenia. This may imply the decrease of trace amine synthesis resulting to the reduced stimulation of TAAR1 on terminals of midbrain VTA DA neurons, and may lead to mesolimbic DA hyperactivity in schizophrenia. The decrease of striatal D-neurons of postmortem brains of schizophrenia might be due to neural stem cell dysfunction in the subventricular zone of lateral ventricle. The new “D-cell hypothesis”, in which D-neurons and TAAR1 are involved, may explain mesolimbic DA hyperactivity of schizophrenia.
Biography Keiko Ikemoto M.D., Ph.D. graduated from Shiga University of Medical Science in 1985, and specialized in Psychiatry and Neuroscienc. She studied monoamine neuronal system and sleep as a Boursiere du Gouvernement Francais in the Department of Experimental Medicine, Claude Bernard University (Prof. Michel Jouvet), in France. She is Chief Director of the Department of Psychiatry, Iwaki Kyoritsu General Hospital, in Japan, senior researcher in Fukushima Medical University School of Medicine in Japan. She has published more than 60 papers in the field for neuropsychiatry and neuroscience.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 101 C. Gopi Mohan, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Harnessing human N-type Ca2+ channel receptor by identifying the atomic hotspot regions for its blocker design C. Gopi Mohan Amrita Vishwa Vidyapeetham University, India
oltage-gated N-type Ca2+ channels (NCCs) play dominant roles in neuropathic pain and cerebral ischemia. Ion channel Vtherapeutics for many pathophysiological conditions exists, which include: affective disorders, allergic disorders, autoimmune diseases, epilepsy, hypertension, insomnia, pain, anesthesia, anxiety, and stroke. Experimentally, it was well established that NCC inhibitory activity is essential for the treatment of chronic neuropathic pain and stroke. A major obstacle with these membrane proteins is that the atomic resolution experimental structures are not available to understand the mode of small molecule binding at its active sites. Based on these observations, we have developed for the first time the structure of the closed state of the NCC receptor at the pore forming domains which mainly involve three transmembrane helices (TMhs) S5, P and S6. Hot-spot binding site residues of this receptor model were identified by molecular docking technique using amlodipine, cilnidipine and nifedipine compounds known to be potent Ca2+ channel antagonists. Further, the Ca2+ ion permeability and the hydrophobic gating mechanism provided better structural and functional insights on the NCC receptor. These results are in consonance with other Ca2+ channel receptors and would provide guidance for further biochemical investigations.
Biography C Gopi Mohan is currently an Associate Professor at Amrita Centre for Nanoscience and Molecular Medicine specializing in the area of structural bioinformatics, Chemoinformatics, Nanoinformatics and its biomedical applications. Currently, his team at centre focuses on: Structure-based Drug design, Pharmacophore modeling, QSAR modeling and Nanomaterial modeling using different in silico techniques. He worked as a faculty member of National Institute of Pharmaceutical Education & Research (NIPER), Mohali, Punjab and also as a post doctoral fellow in Indian Institute of Science, Bangalore; University of Bath, UK and CNRS research fellow at University Henri Poincare, France. He had been recipient of Indo-Finland grant for computational biology related to drug development and visited University of Helsinki and University of Turku to complete successfully this collaborative bilateral program. His protein models and other related computational work was appreciated by US based pharmaceutical company leading to future collaboration. He was also cited as international well known expert in the field of Structural Bioinformatics and Chemoinformatics by Synergix Ltd. United Kingdom, which was founded by Dr. N.C. Cohen, a pioneer of rational drug design.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 102 Nils Hansen, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Discovery of small molecule inhibitors of protein-protein interactions using DNA-encoded chemical libraries Nils Hansen Vipergen ApS, Copenhagen, Denmark
iscovery of small molecule inhibitors of protein-protein interactions (PPIs) has been limited due to technological hurdles. DHere we present the discovery of small molecule (MW< 500 Da) inhibitors of PPIs with IC50 in the μM range from a 2 million compound DNA-encoded chemical library. The screening of the library was performed using a recently developed homogenous binding assay. This format avoids protein target denaturation and matrix binding artifacts associated with conventional heterogeneous binding assays. The screening process relies on target binding only and not on functionality i.e. inhibition of PPI. However, interestingly, the majority of binders discovered are inhibitors of the PPI. Could this indicate that most binders are homing to the so called protein hotspots when the protein target is in native confirmations?
Biography Nils Hansen is the CEO and founder of Vipergen ApS. He is the principal inventor of the enabling YoctoReactor® and Binder Trap Enrichment® drug discovery technology platforms. He previously worked for Praecis Pharmaceuticals Inc., Waltham, MA, USA (now GSK) and Symphogen A/S, Copenhagen, Denmark. He earned his Ph.D. in immunology from the University of Copenhagen, Denmark in 2000 and his M.Sc. in Chemistry and Biotechnology from the University of Aarhus, Denmark in 1996.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 103 Ibrahim Chikowe et al., Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007
2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA
Post-marketing surveillance of active pharmaceutical ingredients in antimalarial drugs used in Malawi Ibrahim Chikowe University of Ghana, Ghana
he use of poor quality antimalarials causes low bioavailability of the active pharmaceutical ingredients (APIs) to the drug Ttargets resulting in treatment ineffectiveness or failure and parasites’ resistance over a short period of drug usage. Resistance has rendered the hitherto cheap and effective drugs like chloroquine and sulfadoxine/pyrimethamine replaced with the expensive artemisinins in combination with some alkaloids; artemisinin-based combination therapy (ACT) for malaria treatment. High cost of the ACTs has made them attractive to counterfeiters leading to the proliferation of poor quality antimalarials on the drug markets. 112 samples of antimalarial drugs were purchased from licensed and unlicensed markets in selected parts of the country. Samples were subjected to visual inspection and registration verification with the regulatory board. Basic tests, semi-quantitative thin layer chromatography (SQ-TLC) and high performance liquid chromatography (HPLC) tests were conducted to quantify the APIs in the samples. The results showed an 85 % registration status with all samples purported to be imported. In addition, all samples complied with visual inspection requirements and basic tests. Generally, approximately 95.12% of the artemether/lumefantrine containing samples had failed the tests, with dihydroartemisinin/piperaquine phosphate, dihydroartemisinin/sulfadoxine/pyrimethamine, sulfadoxine/pyrimethamine, artesunate/sulfadoxine/pyrimethamine and quinine containing samples having failure rates of 64.30%, 100%, 91.30%, 88.9% and 53.8% respectively, resulting to an overall 85.71% failure rate. Therefore, the tests confirmed the presence of requisite APIs in all the drugs and wide spread circulation of poor quality antimalarial drugs in Malawi with dihydroartemisinin/sulfadoxine/pyrimethamine containing samples being more compromised.
Biography Ibrahim Chikowe is a student of Master of Philosophy in Chemistry at the University of Ghana, from Malawi being sponsored by DFID/Wellcome trust under the Health Research Capacity Strengthening Initiative (HRCSI) through National Commission for Science and Technology in Malawi. He is awarded with research fellowship to pursue medical chemistry at any African university in 2011 and expected to graduate in November, 2013.
Med chem 2013 MedChem & CADD-2013 Volume 3 Issue 4 October 15-17, 2013 ISSN: 2161-0444, Med chem an open access journal Page 104