244th OMICS Group Conference 3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Scientific Tracks & Abstracts (Day 1)
MedChem & CADD-2014 Page 21 Track 1 & 2 Day 1 December 08, 2014 1: Rational Drug Design 2: Computer-Aided Drug Design and Structure Determination Session Chair Session Co-Chair Patrick Y S Lam Concepción González-Bello Drexel University, USA University of Santiago de Compostela, Spain Session Introduction Title: Predicting ligand binding affinity: A comparative study on the use of docking vs. Bayesian categorization and random forest recursive partitioning David C Kombo, Proteostasis Therapeutics, Inc., USA Title: In silico screening for anti-HPV agents using pharmacophore models Tatsuya Takagi, Osaka University, Japan Title: NMR driven conformational design - A powerful drug design tool Thorsten Nowak, C4X Discovery Holdings PLC., UK Title: Computer aided design and optimization of kinase and phosphatase inhibitors Kal Ramnarayan, Sapient Discovery, LLC., USA Title: The use of epitopes against schistossomiasis: The role of molecular modelling Moacyr Comar Junior, Federal University of São João del Rei, Brazil Title: Bacterial type II dehydroquinase enzyme: From the reaction mechanism to the structure-based design of inhibitors Concepción González-Bello, University of Santiago de Compostela, Spain
MedChem & CADD-2014
Page 22 David C Kombo, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Predicting ligand binding affinity: A comparative study on the use of docking vs. Bayesian categorization and random forest recursive partitioning David C Kombo Proteostasis Therapeutics, Inc., USA
iming at comparing ligand-based design (LBD) and structure-based design (SBD) methods, we have carried out Adocking into homology models and Bayesian categorization to predict ligand binding at various human and rat nicotinic acetylcholine receptor subtypes. We found that although results vary with receptor subtype, Bayesian categorization exhibits higher accuracy and enrichment than unconstrained docking into homology models. However, docking accuracy is improved when one sets up a hydrogen-bond (HB) constraint between the cationic center of the ligand and the main-chain carbonyl group of the conserved Trp-149 or its homologue (a residue involved in cation-π interactions with the ligand basic nitrogen atom). This finding suggests that this HB is a hallmark of nicotinic ligands binding to nAChRs. We also found that ligand- based Bayesian-derived enrichment factors and structure-based docking-derived enrichment factors highly correlate to each other. Moreover, they correlate with the mean molecular fractional polar surface area of actives ligands and the fractional hydrophobic/hydrophilic surface area of the binding site, respectively. We are extending our studies by comparing LBD methods Bayesian categorization and recursive partitioning random forest with SBD docking into binding sites of proteins with experimentally-derived three-dimensional structure. [email protected]
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 23 Tatsuya Takagi et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
In silico screening for anti-HPV agents using pharmacophore models Tatsuya Takagi and Norihito Kawashita Osaka University, Japan
PV (Human Papillomavirus) is known as one of the papillomavirus family which is able to infect humans. HPV infection Happears to be a necessary prerequisite for more than 90% of cervical cancer, especially squamous cell carcinoma. 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. Last year, at this conference, the author reported some candidate compounds which can be HPV E6 protein inhibitors developed by using in silico screening, especially, docking studies. However, 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. Thus, in this study the author tried to develop other candidates of HPV E6 protein inhibitors which can be more drug- like using in silico drug-like compounds database. Some lead chemical structures, which appeared to be effective not only for revealing the mechanism of canceration of HPV infected cells, but also for some key compounds of anti-HPV E6 inhibitors were obtained.
Biography Tatsuya Takagi completed his PhD at the age of 32 from Osaka University. He was an Assistant Professor 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 is serving as Chairman of Division of Structure-Activity Relationship of the Pharmaceutical Society of Japan.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 24 Thorsten Nowak, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
NMR Driven conformational design - A powerful drug design tool Thorsten Nowak C4X Discovery Holdings PLC., UK
lear and detailed understanding of dynamic 3D small molecule in solution and the dynamic interchange of accessible Clow energy conformations have traditionally been predicted computationally or extrapolated from small molecule crystal structure data. The impact of a new quantitative and precise technology is described that provides detailed information of ligand conformations in solution. When coupled with activity data it gives unprecedented accuracy in describing pharmacophoric information that can deliver high impact, in for example, drug design contexts. The necessary experimental information required to define solution conformation is extracted from one & two-dimensional NMR data of ligand molecules in physiologically relevant solution conditions. In addition to driving drug design, conformational information on ligand molecules can be applied to broad settings in drug discovery enabling the identification of chemical equity independently of general screening approaches to template-hopping and virtual screening. Furthermore, it can significantly impact on small molecule drug design in Lead Generation and Lead Optimisation independently or in conjunction with computational chemistry or structure based drug design approaches. The presentation details the application of the technology and describes the use and impact with a number of case studies in the areas of structure based design and GPCR targeting settings.
Biography Thorsten Nowak completed his PhD from the University of Cambridge (UK) in the areas of aldol methodology and natural product synthesis. In 1996 he joint AstraZeneca where he worked on all stages of drug discovery from target to candidate selection in medicinal chemistry as team leader and project manager. His keen interest in new technologies motivated a career move from big pharma to platform technology business in 2012 when he joint C4X Discovery. In his current role he is responsible for all internal drug discovery projects at C4X Discovery as well as continued development of the technology in the context of application to drug discovery.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 25 Kal Ramnarayan, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Computer aided design and optimization of kinase and phosphatase inhibitors Kal Ramnarayan Sapient Discovery, LLC., USA
inases and phosphatases are implicated in several disease states and a number of publications and patents have been Kpublished on the discovery of novel inhibitors for these classes of proteins. Newer targets are also coming into play with a need for small molecule inhibitors. More than 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 kinases and phosphatases. Lessons learned with these targets will be valuable in attempting to discover novel inhibitors to newly discovered kinases and phosphatases.
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 ImmunoPharmaceutics 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 PhD 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.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 26 Moacyr Comar Junior, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
The use of epitopes against schistossomiasis: The role of molecular modelling Moacyr Comar Junior Federal University of São João del Rei, Brazil
he schistossomiasis is an important parasitic disease that affects more than 200 million people around the world in 76 Tcountries. The primary weapon used against Schistossoma mansoni is chemotherapy, but reinfections and occurrence of drug resistant parasites was related. Thus, thevaccines using the epitopes existing in the parasitic tegument could be effective against this disease. The main event where the epitopes can be used against schistossomiasis is its interaction with theMHC class II complex (MHC-II). Then, the complex formed by MCH/epitope would interactwith the TCR (T cell receptor) triggering one immunization cascade. These interactions arefundamental to development of any kind of vaccine based on the epitopes and the understandinghow it occurs is mandatory for this process. The contribution of the bioinformatics and molecular modeling (MM) can be helpful in the sense to improve the knowledge about the interaction ofthe epitopes with MHC complex because the molecular modelling tools can provide information about binding energy, unbinding process, orbital energies and electrostatic interaction amongothers. In addition, the use of molecular modelling results can decrease the amount ofexperimental work providing some insights about what kind of epitopes use and why use them. Keeping this in mind, this speak attempt to show what have been done in the study of interactionbetween epitopes and MCH-II involving bioinformatics, molecular docking, molecular dynamicsand quantum chemical calculations. Besides, some experimental results will be compared withtheoretical ones.
Biography Moacyr Comar Junior has completed his PhD at the age of 31 years from University of São Paulo. At the end of PhD he went to Amazonas to work in the Theoretical Chemistry Lab at theFederal University of Amazonas. In 2009 he went to Federal University of São João del Rei tothe Molecular Modeling Lab. He has published articles about different subjects in reputedjournals and has been serving as reviewer member of some journals of biotechnology.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 27 Concepción González-Bello, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Bacterial type II dehydroquinase enzyme: From the reaction mechanism to the structure-based design of inhibitors Concepción González-Bello Universidad de Santiago de Compostela, Spain
he decreased effectiveness of antibacterial agents against infectious diseases caused by the development of drug resistance Thas become one of the most important public health issues of the early 21st century. Despite the recognized need for new antibiotics, only a few new classes of antibiotics have been brought to the market in the last three decades. Therefore, the discovery of novel drugs and therapies to treat antibiotic-resistant infections and, particularly of drugs with new mechanisms of action is needed. Today, there is a great and increasing interest in the detailed knowledge of the catalytic mechanism of selected enzymes for the rational design and development of new inhibitors that can be used as drugs. In recent years, computational methods have consolidated their value as important complementary tools that can assist in the elucidation of how these reactions are catalyzed and to derive QSAR models that help rationalize the determinants of binding affinity for inhibitors. Here we report results from computational, structural and biochemical studies that help understand in atomic detail the catalytic mechanism of two essential bacterial enzymes that are recognized to be attractive targets for the development of new antibacterial agents, the type II dehydroquinase enzyme (DHQ2). Comparative Binding Energy (COMBINE) analysis to quantify the importance of the hydrogen bonding interaction of the ligands with the water molecule involved in the enzymatic mechanism and the application of this knowledge in the structure-based designed of inhibitors will be also presented.
Biography Concepción González-Bello has obtained her PhD 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 a postdoctoral stay in the University of Cambridge (UK) with Prof. Abell, she joined USC as an Assistant Professor, was promoted to Associate Professor in 2003 and obtained the Spanish habilitation to full Professor in 2011. She is author of more than 50 papers and several book chapters. She is a member of the ChemMedChem International Advisory Board.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 28 Track 3, 4, 8 & 9 Day 1 December 08, 2014 3: Quantitative Structure-Activity Relationships 4: Advanced Medicinal Chemistry 8: Drug Interactions and Drug Metabolism 9: Neurodegenerative Diseases Session Chair Session Co-Chair Thorsten Nowak Istvan J Enyedy C4X Discovery Holdings PLC., UK Biogen Idec, USA Session Introduction Title: Structure-based design of covalent inhibitors or protein-protein interactions Maurizio Pellecchia, Sanford-Burnham Institute for Medical Research, USA Title: Revisiting INH: QSAR-based design of new anti-tubercular compounds Filomena Martins, Universidade de Lisboa, Portugal Title: In vitro COX inhibitory activity of novel α-aminoarylpropionic acid derivatives A G Zhamharyan, Yerevan State Medical University, Armenia Title: New developments in docking and scoring Istvan J Enyedy, Biogen Idec, USA Title: Comparative molecular modeling study between the pre-fusion and post-fusion conformations of newcastle disease virus: Homology modeling, and virtual screening Mohammed A Khedr, King Faisal University, KSA Title: Peptide-displaying phage technology in breast cancer diagnosis Thaise Gonçalves Araújo, Federal University of Uberlandia, Brazil Title: Discovery of small molecule blockers of protein-protein interactions using DNA-encoded small- molecule libraries Nils Hansen, VipergenApS, Denmark Title: Neuroprotective properties of compound isolated from Dianthus superbus L. Choong Je Ma, Kangwon National University, Korea Title: Investigation of human CA1-induced toxicity in the Drosophila model of motor neuron degeneration Jian Liu, Xi’an Jiaotong-Liverpool Univeristy, China
MedChem & CADD-2014
Page 29 Maurizio Pellecchia, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Structure-based design of covalent inhibitors or protein-protein interactions Maurizio Pellecchia Sanford-Burnham Medical Research Institute, USA
hile protein-protein interactions (PPIs) represent in principle a significant number of potential drug targets, their Wvalidation is usually hampered by the lack of suitable pharmacological tools with sufficient potency and proper pharmacological properties. HTS and other screening methods traditionally failed at identifying such agents. It is reported in this study that a combination of biophysical methods supported by structural studies can guide the design and synthesis of novel pharmacological tools targeting PPIs. When possible, we found that the design of covalent inhibitors can dramatically increase potency and selectivity of these agents. Examples will be discussed including the E3 ubiquitin ligase Siah, the anti- apoptotic protein Bfl-1, and the EphA4 ligand binding domain. For the first two targets, structure-based design of peptide mimics ultimately led to potent and selective antagonists. For the EphA4 LBD, we also deployed a novel NMR-based screening method of combinatorial libraries that together with structural studies led to a potent inhibitor with in vivo activity.
Biography Maurizio Pellecchia is a medicinal chemist with strong background in biophysics and structure-based drug design. He obtained his PhD in Pharmaceutical Sciences, at the ETH-Zurich, and the University of Michigan. Prior to his recruitment at the Sanford-Burnham in 2002 as Associate Professor, he spent a few years in the pharmaceutical industry. He is currently Professor of Chemical Biology at the Cancer Center of the Sanford-Burnham Medical Research Institute, and is an Adjunct Professor at the Department of Pathology of UCSD, and teaches two graduate courses in drug design.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 30 Filomena Martins, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Revisiting INH: QSAR-based design of new anti-tubercular compounds Filomena Martins Universidade de Lisboa, Portugal
uberculosis (TB) ranks as the second leading cause of death from a single infectious agent, the Mycobacterium tuberculosis T(Mtb). WHO reports 8.6 million new TB cases and 1.3 million deaths worldwide in 2012. The emergence of multidrug resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has reduced considerably the number of available drugs for treatment, making the quest for “new”, effective and non-toxic drugs a major concern. Despite the significant progresses made in the last ten years in the development of new anti-TB drugs, with several compounds reaching phases 2 and 3 of the clinical pipeline, the truth is that isoniazid (INH), firstly synthesized in 1952, remains one of the most effective drugs to treat TB. Any new compound derived from INH that proves to be active against several forms of tuberculosis, would certainly be less problematical than totally new compounds with unknown long-term effects as those recently introduced in therapeutic combination regimens. In this work we show how a judicious and well-validated QSAR methodology can be used to successfully design new INH-based derivatives with better activitiesthan the parent compound against both susceptible and resistant Mtb strains. Also, some evidences will be presented that question the putative increase in resistance of katG (S315T) towards INH, when compared with wtkatG.
Biography Filomena Martins has obtained her PhD at the University of Lisbon in 1993. She did postdoctoral work with Prof. Michael Abraham at the University College London and Dr. Robert Mitchell at SmithKline Beecham Pharmaceuticals at Welwyn, Hertfordshire, UK. She is currently Assistant Professor at the University of Lisbon where she is responsible for the Structure and Reactivity Group of the Chemistry and Biochemistry Centre. Her present research interests include the development of judicious and well validated quantitative structure-property relationships (QSPRs) to design (and synthesize) new molecules with better biological or physicochemical performance. She has more than 40 publications in the areas of Physical and Medicinal Chemistry.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 31 A G Zhamharyan et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
In vitro COX inhibitory activity of novel α-aminoarylpropionic acid derivatives A G Zhamharyan1, M G Balasanyan1, L G Zhamharyan2, A S Sagian2 and H V Topchyan1 1Yerevan State Medical University, Armenia 2NAS, Armenia
he structure activity relationship of NSAIDs evidences that arylpropionic acid derivatives - one of the wide used group for Ttreatment of inflammation diseases, possess cycloxygenase inhibiting activity. In view of this, in previous investigations it was synthesized the new derivatives of α-aminoarylpropionic acid and assessed their pharmacological activity. Obtained results demonstrated in vivo anti-inflammatory and anti-nociceptive activities of novel synthesized α-aminoarylpropionic acid derivatives. In presented work it was studied in vitro COX-1 and COX-2 inhibitory activity of mentioned compounds. The COX inhibitory activity was measured using COX Inhibitor Screening Assay Kit, according to the protocol. Experimental data evident that testified compounds possess both human recombinant COX-1 and COX-2 non selective inhibitor activity (IC 50˂10 μM), with different affinity to COX isoforms. The phenyl-alanine derivative appear comparable more activity to COX1 (IC 50=1.9 μM). The S-triazole derivative shows a highest inhibitor activity with more selectivity to COX 2 (IC 50=0.9 μM). Thus, the study suggests that triazoles derivatives of α-aminoarylpropionic acid could be used as a starting point for the development of novel COX inhibitors.
Biography A G Zhamharyan has completed her PhD at the age of 29 years from Yerevan State Medical University and now preparing postdoctoral studies from the same university. She is the head of Department of Pharmacy in Yerevan State Medical University. She has published more than 25 papers in reputed journals connecting to study of the natural and chemical compound anti-inflammatory and anti-nociceptive activities.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 32 Istvan J Enyedy et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
New developments in docking and scoring Istvan J Enyedy1 and Mark Mc Gann2 1Biogen Idec, USA 2OpenEye Scientific, USA
ver the last two years, we have set up about 300 internal structures and more than 10, 000 compounds for testing docking Oand scoring strategies. We used this set for evaluating the new scoring function CHEMGAUSS5 implemented into FRED and HYBRID from OpenEye. The presentation will show the improvements that obtained using the latest scoring function when compared to CHEMGAUSS4, the correlation of a few components of the scoring function with IC50, the impact of using information from solvent mapping to guide docking, and recommended statistical analysis for estimating errors in docking runs.
Biography Istvan J Enyedy has been involved in new target evaluation, hit finding, and hit-to-lead optimization projects for proteins from several target classes using both ligand and structure-based methods. He is coauthor of more than 30 publications and 11 patents/applications. He received his PhD 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.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 33 Mohammed A Khedr et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Comparative molecular modeling study between the pre-fusion and post-fusion conformations of Newcastle disease virus: Homology modeling, and virtual screening Mohammed A Khedr, Bander E Al-Dhubaib and Ibrahim A Al-Alhaider King Faisal University, KSA
aramyxoviridae family is a large family that has many important viruses. The viruses of this family are the main cause of Pdifferent human diseases such as respiratory tract infections, pneumonia. New castle disease virus causes a severe disease occurs in both domestic, wild animals and may affect human as well. New castle disease virus is a typical paramyxo virus with an enveloped single stranded, negative sense RNA genome. The RNA genome has six genes; nucleocapsid protein, phosphoprotein, matrix protein, polymerase protein, hemagglutinin-neuraminidase protein, and fusion protein. After the binding of virus to the host cell byhemagglutinin-neuraminidase protein, the fusion protein will be involved in a membrane fusion process. This will be followed by an irreversible conformational change from a metastable fusion conformation to a post stable, low energy conformation. This process is very important for the viral virulence. To date there is neither vaccination nor selective antiviral drug for this virus. The design of an inhibitor that can bind to this fusion protein and prevent the conformational change will inhibit the virus. This work aims to design such inhibitor starting by a comparative molecular modeling analysis of the pre and post fusion conformations. Homology modeling study was done to build the pre-fusion conformation. Molecular dynamic simulations were performed to compare between the most stable conformers. Structure-based virtual screening was performed to screen large number of compounds against the built model. Finally, the top-scored hits were selected for biological testing. All the molecular modeling studies were done by MOE 2013.08.
Biography Mohammed A Khedr is the coordinator of drug design at College of Pharmacy, King Faisal University. He did his PhD in ‘’Computer-aided drug design and synthesis of novel antivirals’’ in Cardiff University, UK. He was trained in Oxford University, UK on the recent advances in drug design. He discovered novel inhibitors of West Nile Virus by de novo approach and was an oral speaker in ‘’The 2nd International Ligand-based and Fragment-based drug design international conference, Oxford, UK, 2013’’. He is the PI of two research projects funded by King Faisal University. He has supervised a number of master, PhD, and student projects at different universities.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 34 Thaise Gonçalves Araújo et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Peptide-displaying phage technology in breast cancer diagnosis Thaise Gonçalves Araújo1, Emília Rezende Vaz1, Galber Rodrigues Araújo1, Vanessa da Silva Ribeiro2, Yara Cristina de Paiva Maia3 and Luiz Ricardo Goulart1 1Federal University of Uberlandia, Brazil 2Federal University of Goias, Brazil 3University of California Davis, USA
hage display is a molecular technique by which foreign proteins are expressed at the surface of phage particles. This is an Pextremely powerful tool for selecting peptides with specific binding properties from vast numbers of variants. Considering tumors, is a promise technology in selecting targets with clinical relevance, able in recognize molecular diversity of cancer. It has been characterized by phage display a new FabC4 antibody with clinical relevance in diagnostics, disease staging, and prognosis. However, further characterization of its target is essential for BC management. In this study, a biopanning assay against FabC4 using PH.D-12 library was performed. To isolate peptides that recognize our FabC4 antibody, a subtractive selection procedure was applied against an irrelevant Fab, and the elution of ligands was performed in two steps: with non- malignant proteins, which were discarded, and with BC proteins, which were amplified. It was shown, by Phage-ELISA, that six clones differentiated sera samples from 50 patients with BC, benign disease, and from health women. Chemically synthesized peptides were specifically direct against FabC4, and tested against 150 patients. Absorbance for sera from patients with BC was significantly higher than samples from benign disease and health women. Obtained results open new perspectives in BC diagnostic, target therapy and demonstrate the selective of the applied procedure. The use of synthetic peptides proved to be an excellent assay that was reproducible, simple, fast, and inexpensive, and it can be applied in diagnostic and therapeutic programs.
Biography Thaise Gonçalves Araujo has completed her PhD at Federal University of Uberlandia, Brazil in 2012, working with breast cancer and phage display technology. She collaborated with NIH developing projects with phage display and HIV antibodies. She has published papers incancer areas and is professor of the Federal University of Uberlandia.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 35 Nils Hansen, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Discovery of small molecule blockers of protein-protein interactions using DNA-encoded small- molecule libraries Nils Hansen Vipergen ApS, Denmark
iscovery of small molecule blockers of protein-protein interactions (PPIs) has been limited due to technological hurdles. DHere we present the discovery of small molecule blockers of PPIs with potencies in the nanomolar-micromolar range from multi-million compound DNA-encoded small-molecule libraries. The screening of the libraries was performed using a homogenous (immobilization-free) binding assay relying on a unique principle of trapping the binding complexes-small molecule and target protein-in miniscule droplets using emulsion technology. This format provides a very low false positive rate by avoiding 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. However, interestingly, a large fraction of the hits discovered are in fact blockers of the PPI. Case stories will be presented including the first and only reported IL-17A small molecule blockers.
Biography Nils Hansen is the CEO and founder of VipergenApS. 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 PhD in immunology from the University of Copenhagen, Denmark in 2000 and his MSc in Chemistry and Biotechnology from the University of Aarhus, Denmark in 1996.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 36 Choong Je Ma et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Neuroprotective properties of compound isolated from Dianthus superbus L. Choong Je Ma, Bo-Ra Yun, Hye Jin Yang, Jin Bae Weon, Min Rye Eom and Youn Sik Jung Kangwon National University, Korea
ianthus superbus L. has been used in Chinese herbal medicine as a diuretic and anti-inflammatory agent. Triterpenoid Dsaponins such as dianoside A to I are reported to be among the major bioactive compounds in D. superbus; compounds including dianthosaponins, dianthramide, flavonoid, coumarin, triterpenoid, pyran-type glycoside, and cyclic peptides have also been isolated from D. superbus. In this study, we isolated bioactive compound from D. superbus and evaluated neuroprotective activity against glutamate-induced cell death in the hippocampal neuronal HT22 cells. New compounds, chrysoeriol-5- methylether-7-O(2’’, 6’’-di-O-α-l-rhamnopyranosyl)-β-d-glucopyranoside (2) isolated by bioactivity-guided separation. Structure of compound was identified on the basis of 1H-NMR, 13C-NMR, and 2D NMR spectra, while neuroprotective properties were evaluated by performing the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. We also evaluated reactive oxygen species (ROS) generation, AChE inhibition, DPPH radical and H2O2 scavenging activity to elucidate possible mechanism of effect. Chrysoeriol-5-methylether-7-O(2’’, 6’’-di-O-α-l-rhamnopyranosyl)-β- d-glucopyranosideeffectively protected HT22 cells against glutamate toxicity. Additionally this compound significantly decreased the ROS level in the oxidative stress induced HT22 cells by glutamate and showed antioxidantive effect (DPPH radical and H2O2 scavenging effect) and acetylcholinesterase inhibition. In conclusion, chrysoeriol-5-methylether-7-O(2’’, 6’’-di-O-α-l-rhamnopyranosyl)-β-d-glucopyranoside isolated from D. superbus extract exhibited neuroprotective effect via antioxidant system, inhibition ROS. Further studies may need to elucidate the possible mechanism of effect ofchrysoeriol-5- methylether-7-O(2’’, 6’’-di-O-α-l-rhamnopyranosyl)-β-d-glucopyranoside. Overall results of study suggested that chrysoeriol- 5-methylether-7-O(2’’, 6’’-di-O-α-l-rhamnopyranosyl)-β-d-glucopyranoside has therapeutic potential for applications in neurodegenerative diseases.
Biography Choong Je Ma has completed his PhD at the age of 32 years from Seoul National University and postdoctoral studies from University of Michigan. He is the professor of Department of Medical Biomaterials Engineering, College of Biomedical science, Kangwon National University, Korea. He has published more than 20 papers in reputed journals.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 37 Jian Liu, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Investigation of human CA1-induced toxicity in the Drosophila model of motor neuron degeneration Jian Liu Xi’an Jiaotong-Liverpool Univeristy, China
myotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is one of the neurodegenerative diseases that affect Amotor neuron function leading to paralysis and fatal death. Mechanisms of ALS pathogenesis remain elusive. Carbonic anhydrase I (CA1) was recently discovered to be altered in ALS patients. Whether and how CA1 might be involved in ALS pathology is completely unknown. Our study demonstrated for the first time that CA1 was expressed in spinal cord motor neurons. We further established Drosophila model of CA1-induced motor neuron degeneration and investigated molecular mechanisms of pathology. Our results showed: 1) Expression of human CA1 in Drosophila motor neurons caused locomotion defect in both larval and adult flies without affecting lifespan; 2) Impairment of larval locomotion is correlated with reduced numbers of boutons and branches at NMJs, while preliminary data also indicated that the number of adult motor neurons was decreased by CA1 expression. 3) CA inhibitor acetazolamide ameliorated larval locomotion defect in Drosophila suggesting that carbonic anhydrase activity was required for the toxicity. Results from our studies provide potential new drug targets and design for therapeutic treatment of ALS.
Biography Jian Liu has completed her PhD in Neuroscience from Washington University and postdoctoral studies from University of California, San Diego.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 38 Isidro Cortes-Ciriano et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Applications of proteochemometrics: From species extrapolation to cell line sensitivity modelling Isidro Cortes-Ciriano, Gerard J P Van Westen, Daniel S Murrell, Eelke BLenselink, Andreas Bender and Therese EMalliavin
roteochemometrics (PCM) is a computational method to simultaneously model the bioactivity of multiple ligandsagainst Pmultiple protein targets, and therefore permits to explore the selectivity and promiscuity of ligands on different protein classes. Indeed, the simultaneous inclusion of both chemical and target information enables the extra- andinterpolation to predict the bioactivity of compounds on targets, which can be not present in the training set. In thiscontribution, we will firstly show a methodological advance in the field, namely how Bayesian inference (GaussianProcesses) can be successfully applied in the context of PCM for (i) the prediction of compounds bioactivity along withthe error estimation of the prediction; (ii) the determination of the applicability domain of a PCM model; and (iii) theinclusion of experimental uncertainty of bioactivity measurements. Additionally, we will describe how the applicationof PCM can be useful in medicinal chemistry to concomitantly optimize compounds selectivity and potency, in thecontext of two application scenarios, which are: (a) Modellingisoform-selective cyclooxygenase inhibition; and (b)large-scale cancer cell line drug sensitivity prediction.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 39 Sonal Dubey, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Data and compute intensive escience approaches in computational medicinal chemistry Scott James Lusher Netherlands eScience Center, The Netherlands
Science is an inherently multi-disciplinary pursuit concerned with the use of compute-intensive methods to enable data- edriven science. The challenge of eScience is to ensure that the most value can be gained from all new scientific endeavors by using information technology (IT) to improve experimental design, data management, data analysis and communication as well as to model and simulate complex systems and behaviors. Medicinal chemistry, like most scientific disciplines, is becoming increasingly data-intensive and dependent on our capacity to manage and exploit growing data resources. In particular, there is increasing need for drug-discovery organizations to enable decision making that is informed by the growth of their internally generated data and its integration with external data. This talk will explore the latest developments in eScience in the context of drug-discovery and how advanced computing and data-driven methods will increasingly impact chemical exploration and rational design.
Biography Scott James Lusher worked in pharmaceutical R&D (Organon, Schering-Plough and Merck) for ten years (2001-2011) providing the molecular basis and rationale for the selection and design of NCEs within cross-disciplinary projects. Additionally, he had a role ensuring the strategic management and project implementation of molecular informatics within research. He joined the Netherlands eScience Center in 2011 as part of its management team and is currently Director Applied eScience developing new scientific applications of ICT. He has a part-time appointment at the Radboud University Medical Center and has a PhD in computational drug design from the same institute.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 40 Sonal Dubey, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Synthesis, biological evaluation and 3D QSAR of some novel benzimidazole derivatives as anti- microbial compounds Sonal Dubey1, Vishwa Prakash2 and Preethi GB2 1Krupanidhi College of Pharmacy, India 2 KLEU’s College of Pharmacy, India
enzimidazoles are an important group of heterocyclic compounds that are biologically active and of significant importance Bin medicinal chemistry. In light of affinity they display towards a variety of enzymes and protein receptors, medicinal chemists should certainly classify them as privileged ‘substructures’ for drug dosing. The incorporation of the nucleus is an important synthetic strategy in studies of antimicrobial drug discovery. In the past few decades, benzimidazole and its derivatives have received much attention due to their chemotherapeutic values. We have synthesized p-substituted acetanilide, p-substituted nitro acetanilide, p-substituted nitro aniline, p-substituted phenylenediamine. There after substituted mercaptobenzimidazoles and thio-methyl-pyridine substituted benzimidazoles were synthesized from these were synthesized by cyclization and condensation reactions. All these newly synthesized derivatives were confirmed by IR, H-NMR and mass spectra. Antimicrobial study of these compounds against Gram +ve and Gram -vemicro organisms and using ciprofloxacin as standard.Someof the compounds showed moderate activity. With an objective to generate computational model, which can be used to design new derivatives in the series using the data accumulated by the current study, it wasintended to do a computational 3D-QSAR studies. The models generated by TopomerCoMFA were in the form of contour plots which showed the requirement of steric and electrostatic fields in the different regions of the fragments formed during the study with an r2of 0.725-0.843 and q2 of 0.610-0.636. All the models generated, demonstrated goodpredictivity which suggests that our approaches may be beneficial for discovery of novel molecules on the path of rational drug discovery which can ultimately save time, money and efforts at wet lab end.
Biography SonalDubeyhas completed PhD in 2003. Since then she is actively involved in academics and research. She is presently working as Professor and HOD of Dept. of Pharm. Chemistry, at Krupanidhi College of Pharmacy. She has published one book, more than 30 papers in reputed journals and has been serving as an editorial board member of repute.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 41 244th OMICS Group Conference 3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Scientific Tracks & Abstracts (Day 2)
MedChem & CADD-2014 Page 44 Track 5 & 6 Day 2 December 09, 2014 5: Cancer Research in Medicinal Chemistry 6: New Approaches in Drug Discovery Session Chair Andrew B McElroy Eligochem Ltd., UK Session Introduction Title: Research and development for preparation and preclinical evaluation of novel low-molecular-weight phospha sugar antitumor agents targeting IER5/Cdc25B Mitsuji Yamashita, Shizuoka University, Japan Title: Strategies to optimize and use bacterial cytochromes p450 for drug discovery & development Nico P E Vermeulen, VU University Amsterdam, Netherlands
Title: New agonists of the CB2 cannabinoid receptor: Discovery of a new class of analgesic compounds Pier Giovanni Baraldi, w Title: Polar Drugs Andrew B McElroy, Eligochem Ltd., UK Title: Drug discovery against category A-C pathogens through MEP pathway Prabagaran Narayanasamy, University of Nebraska Medical Center, USA Title: Discovery of novel lead compounds by large scale diverse encoded chemical libraries Jin Li, HitGen Ltd., China Title: In silico approach to predict ADME-Tox properties of small organic molecules: Challenges and opportunities for drug discovery Maria Miteva, University Paris Diderot, France
MedChem & CADD-2014
Page 45 Mitsuji Yamashita et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Research and development for preparation and preclinical evaluation of novel low-molecular-weight phospha sugar antitumor agents targeting IER5/Cdc25B Mitsuji Yamashita1, Reiko Makita1, Hiroko Hasegawa1, Michio Fujie2, Satoki Nakamura2, Junko Yamashita1, Tatsuo Oshikawa3, Mitsuru Kondo1, Mitsuo Toda1, Motohiko Kimura1, Kazunori Ohnishi2 and Haruhiko Sugimura2 1Shizuoka University, Japan 2Hamamatsu University School of Medicine, Japan 3 Numazu National College of Technology, Japan
y this research, novel multiple type low-molecular-weight antitumor agents of phospha sugar derivatives, which target BIER5/Cdc25B and innovate in chemotheraputic treatment for cancer patients of various type of cancer cells, are developed. Sugar derivatives, whose oxygen atom in the hemiacetal ring is replaced by a nitrogen or a sulfur atom, etc., are called as pseudo sugars and well investigated. Among pseudo sugars phospha sugars in which the oxygen atom in the hemiacetal ring of sugars is replaced by a phosphorus moiety are not so well investigated in spite of important biological activities being expected for the pseudo sugar analogues. We have developed novel synthetic methodologies for preparing phospha sugar derivatives and constructed their compound library, and then preclinical evaluations have been carried out. Among the compound library of the phospha sugar derivatives, branched novel low-molecular-weight di- and tri-bromo deoxyphospha sugar derivatives (DBMPP and TBMPP) as well as some substituted phospha sugar analogues were found to exert novel, potential, and wide spectral antitumor activities by MTT in vitro evaluation method. The characterization and mechanism elucidation of these phospha sugar derivatives by flow cytometry and Western blotting showed that phospha sugars DBMPP and/or TBMPP enhanced the expression of cancer suppressors and suppressed the expression of cancer accelerators. Phospha sugar derivative TBMPP enhanced the expression of IER5 and then suppressed the expression of Cdc25B, which is the common and essential factor to act at the mitosis stage of the tumor cell cycles. Therefore, phospha sugar derivatives might induce apoptosis at G2/M stage and inhibit various kinds of cancer cells’ growth. In vivo evaluation for TBMPP against K562 cell transplanted to a nude mouse was checked visually to be successful. We are expecting that phospha sugars may be developed to be clinically useful novel antitumor agents.
Biography Mitsuji Yamashita was born in 1944 and has completed his PhD 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, USA. He was a visiting professor of University of Massachusetts at Amherst, USA, and a researcher of Oxford University, UK, in 1994. He was promoted to be a professor of Graduate School of Science and Technology, Shizuoka University, Japan, in 1998 and retired at the age of 65 years old, and he is now a professor emeritus and specially-appointed professor of Shizuoka University, Japan. His research field is now focused on medicinal materials based on chemistry of carbohydrates and heterocycles. He has published more than 175 papers and patents as well as four books. Mitsuji Yamashita is now mainly concentrating in the research and development of phospha sugar antitumor agents and sugar dendritic Gd-DTPA MRI contrast agents for innovating in medical treatment for cancer patients.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 46 Nico P E Vermeulen et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Strategies to optimize and use bacterial cytochromes p450 for drug discovery & development Nico P E Vermeulen, H Venkataraman, D P Geerke and J N M Commandeur VU University Amsterdam, Netherlands
rug discovery and development is a costly and time-consuming process involving many steps, from target discovery up to Dclinical trials. Because drug metabolites often possess pharmacological or toxicological properties, theymay also play an important role in drug action and adverse drug reactions. It is thus important to investigate the metabolism of drugs and drug candidates and to characterize their pharmacological and toxicological properties.Also for the regulatory MIST guidelines, identification, quantification and characterization of major metabolites is considered important. Such studies require large quantities of pure metabolites, which are sometimes difficult to synthesize by conventional chemical methods. Innovative bio- catalytic strategies constitute an alternative for these purposes. Although human Cyt P450s are involved metabolism of many drugs, they are inefficient for the production of large quantities of drug metabolites. Engineered bacterial Cyt P450s, e.g. from Bacillus megaterium (P450s BM3), with high activities and selectivities have better perspectives for large-scale metabolite synthesis. We have developed a ‘metabolic production and profiling platform’ in which libraries of mutant P450 BM3 enzymes are employed for bio-catalytic purposes. Using random mutagenesis, saturation mutagenesis and (computationally guided) site- directed mutagenesis strategies, we have been able to generate versatile, highly active and highly selective and scalable P450 BM3 mutants. Thus we have generated with high turnovers, regio- and stereo-selective metabolites of ionones, pharmacologically active metabolites and toxicologically relevant chemically reactive metabolites. The strategies to engineer and optimize Cyt P450 BM3 mutants and their possibilities and limitations in drug discovery, development and safety studies will be illustrated with selected examples.
Biography Nico P E Vermeulen did a Degree in Chemistry (1975, University of Nijmegen, NL), a PhD in Pharmacology (1980, University of Leiden, NL) and was appointed Professor of Molecular Toxicology in 1985 at VU University Amsterdam. He is Head of Department of Chemistry & Pharmaceutical Sciences. His general research interests are Roles molecular and computational toxicology can play in drug discovery, development and safety assessment. And he got the award like European ISSX Scientific Achievement Award (2006), an Honorary Doctorate (University of Copenhagen, 2011) and is a Life Time Honorary Member of ISSX. His work is taken up in the 2001 and 2014 list of Highly Cited Researchers in ‘Pharmacology’ i.e. the top 1% world-wide.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 47 Pier Giovanni Baraldi et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
New agonists of the CB2 cannabinoid receptor: Discovery of a new class of analgesic compounds Pier Giovanni Baraldi, Giulia Saponaro, Romeo Romagnoli, Delia Preti, Stefania Baraldi, Katia Varani, Pier Andrea Borea and Mojgan Aghazadeh Tabrizi Università di Ferrara, Italy
nterest in the potential medicinal use of cannabinoids grew recently with the discovery of 2 cannabinoid receptors, CB1 and CB . The CB receptor is abundantly expressed in the central nervous system (CNS) and is responsible for the psychotropic I 2 1 side effects. The CB2 receptor is mainly found in cells of the immune system, though it may be upregulated in the CNS under pathological conditions. The main signal transduction pathway triggered is through Gi proteins, resulting in an inhibition of adenylate cylase activity and a decrease in cyclic AMP levels. Recent developments indicate that CB2 receptor ligands have the potential to become therapeutically important. To explore this potential, it is necessary to develop compounds with high affinity for the CB2 receptor. Within a research program to identify novel CB2 agonists, our group designed a hybrid chemical structure that incorporated the structural features of known cannabinoid ligands. The new series of oxazinoquinolone derivatives exhibiting high affinity and selectivity for the CB2 receptor (hCB2 Ki=8.12 nM, hCB1 Ki>10000, selectivity index (SI)>1231). The potency of the new oxazinoquinoline-6-carboxamides was measured in functional assays, revealing that the novel series behaved as CB2 receptor full agonists. The effect of a novel CB2 agonist (MT178) was evaluated in different animal models of pain. In this context, very recently, we have also reported the medicinal chemistry of a series of heteroaryl-4-oxopyridine/7- oxo-pyrimidine derivative which displayed high affinity at the CB2 receptor (hCB2 Ki=11.4 nM, hCB1 Ki=4568, SI=401). In this study, additional CB2 ligands were synthesized by replacing the pyrazolo ring with different heterocycles that were found to be potent CB2 receptor ligands. Moreover, it was shown that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. In 3, 5-cyclic adenosine monophosphate (cAMP) assays, they showed a dose-dependent effect in the modulation of forskolin-induced cAMP production, revealing different behaviors as full agonists, partial agonists and inverse agonists. Finally, we synthesized the structural isomers of our previously reported pyrazolo[3, 4-b]pyridines that allowed us to conduct a pharmacophore exploration and optimization effort around the heteroaryl central scaffold. The newly synthesized 7-oxo-pyrazolo[1, 5-a]pyrimidine-6-carboxamides were tested in competition binding assays toward both rat CB1 and CB2 receptors expressed in native tissues (rat brain or spleen) and human CB1 and CB2 receptors expressed in CHO cells. Affinity data (Ki, nM) were used to calculate the selectivity of newly synthesized compounds for the
CB2 receptors. All of the new compounds showed high affinity and selectivity for the CB2 receptor in the nanomolar range. In 3, 5-cyclic adenosine monophosphate (cAMP) assays, the novel series shows stimulatory effects on forskolin-induced cAMP production acting as inverse agonists.
Biography Pier Giovanni Baraldi received his degree in Chemistry in 1974 from the University of Ferrara, where he held a position of Lecturer in the Faculty of Pharmacy (1977-1980) and Associate Professor of Medicinal Chemistry (1980-1987). In 1987, he became full professor of Medicinal Chemistry at the University of Bologna. In 1992, he returned to the University of Ferrara as full professor of Medicinal Chemistry. His expertise in Medicinal Chemistry is recognized by the important scientific production consisting in more than 410 publications including 60 patents.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 48 Andrew B McElroy, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Polar drugs Andrew B McElroy Eligochem Ltd., USA
his presentation will describe a technology for the systematic design of polar compounds with atypical absorption Tproperties and the application of this technology in a range of drug discovery settings enabling the exploration of novel chemical space with unique advantages.
Biography Andrew B McElroy graduated from Churchill College Cambridge in 1980 with a first class degree in Natural Sciences and completed a PhD in synthetic organic chemistry before joining Glaxo as a medicinal chemist in 1983. He spent seven years at the Ware and Greenford sites working on CNS targets and then three years at the Research Triangle Park in North Carolina as the lead chemist on Cardiovascular projects. He joined Pfizer in Sandwich in 1993 as a manager in the Medicinal Chemistry department. He became Therapeutic Area Lead for Cardiovascular and Neurodegeneration Research, and later on Tissue Repair managing a portfolio of projects up to First in Human. He held leadership roles in chemistry technologies over many years and held global responsibilities for coordinating the continuous improvement of research processes and workflow. At the start of 2009 he became site lead at the Sandwich Site for External Research Solutions group, leading a multidisciplinary team focusing on optimizing external research and in 2011 co-founded TRN - the Research Network Ltd. and in 2012 Eligochem Limited.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 49 Prabagaran Narayanasamy, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Drug discovery against category A-C pathogens through MEP pathway Prabagaran Narayanasamy University of Nebraska Medical Center, USA
he World Health Organization estimates that around 1.5 billion people are currently infected with latent tuberculosis T(TB). Each year, 8 million people develop active disease and of these approximately 20% of the cases are multiple drug resistant and 2% are extensively drug resistant. In all, the annual death toll from TB is 2-3 million people worldwide. However, in spite of recent intensive research no new classes and delivery methods of anti-TB drugs have been developed for clinical use since the 1960’s. In this context, designing, developing and delivering a new drug is very important. To date two different biosynthetic pathways have been reported leading to isopentenyldiphosphate, the universal precursor of isoprenoids. The mevalonate pathway is found in animals whereas the methylerythritol phosphate (MEP) or non-mevalonatepathway is found in many bacteria, some protozoa and plants. Since the MEP pathway is not found in mammalian cells, it is considered an attractive target for the development of antimicrobials, antimalarials and herbicidal agents; a hypothesis that is being explored by raising number of researchers recently. In recent years, we reported enantioselective synthesis of DXP, MEP, CDPME, CDPME2P and MECPP, the substrates for assay development. In addition the kinetic studies of mycobacterial DXS, IspC, IspD, IspE, and IspF were also reported while developing assay. Computational screening against 14 million compounds gave us a good drug lead. With the newly synthesized MEP, CDPME substrate and developed assay a new IspD and IspE inhibitor were discovered showing good IC50 and MIC.
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 PhD 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. He has funding from NIH and also reviewer for proposals.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 50 Jin Li, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Discovery of novel lead compounds by large scale diverse encoded chemical libraries Jin Li HitGen Ltd., China
n this talk, the author will present the design strategy in building a highly diverse, three dimensional and drug-like DNA Iencoded libraries (DELs) to facilitate lead-finding for novel protein target families. Library synthesis methodologies that facilitate incorporation of linking chemistry compatible with DNA integrity will be presented. Computational analysis of the resultant libraries’ molecular properties will be shown. Validation of affinity screening, coding and decoding processes to identify known and novel enzyme inhibitors will be described, along with our early results in affinity screening of this library of >400 million compounds with highly validated protein targets from several protein families.
Biography Jin Li holds 26 years of biopharmaceutical experience (at Protherics and AstraZeneca), with scientific and leadership roles in early stage research; as well as experience in initiating and leading major collaboration and outsourcing programmes. Before founding HitGen, he held Global Director position of Compound Sciences and Computational Sciences at AstraZeneca. This included responsibility for computational chemistry, computational biology and compound collection enhancement for lead generation. He completed his BSc at Sichuan University, and PhD in Macromolecular Sciences at Aston University. Then he completed Post- doctoral research in Theoretical Biochemistry at Manchester University, UK.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 51 Maria Miteva, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
In silico approach to predict ADME-Tox properties of small organic molecules: Challenges and opportunities for drug discovery Maria Miteva University Paris Diderot, France
he progress in computational techniques throughout the past decade enables the use of in silico approaches to predict several TADME-Tox properties of small organic molecules or drug candidates in parallel or prior to experimental investigations. In particular, the availability of three-dimensional structures of some proteins that are key for ADME-Tox events makes possible to perform protein structure-based computations to complement or to go beyond traditional QSAR modeling. We will briefly discuss current in silico methods for ADME-Tox prediction with a focus on drug metabolizing enzymes. Applying structure-based approach to drug metabolizing enzymes is a challenging process because they usually have flexible binding sites. We developed in silico structure-based protocol to gain mechanistic insights from probing small molecules binding to two metabolizing enzymes: the phase I, cytochrome P450 2D6 (CYP2D6), and the phase II, sulfotransferase. We used molecular dynamics to generate suitable diverse protein conformations and protein-ligand docking to discriminate binders and non- binders in large chemical compound collections for CYP2D6 and sulfotransferase. Our results suggest that structure-based in silico approach is useful for prioritizing compounds interacting with drug metabolizing enzymes and may be used to go 'beyond QSAR profiling' of drug candidates to assist decision-making in drug discovery.
Biography Maria Miteva has completed her PhD in 2000 from the Bulgarian Academy of Science, the Institute of Organic Chemistry. She has been working on bioinformatics and drug design in Bulgaria, Sweden and France. She is a Research Director at Inserm (the French institute of health research) and the leader of the team“Virtual screening, PPI & ADMET in silico” belonging to mixed Inserm - University of Paris Diderot, UnitMTi. She has published more than 75 papers in reputed journals and she edited ane-book “In silico lead discovery”. She is a member of the editorial boards of 5reputed journals and an Associated Editor for BMC Toxicology & Pharmacology.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 52 Track 7 & 10 Day 2 December 09, 2014 7: Development and Delivery System 10: Receptors and Inhibitors Session Chair Session Co-Chair Niren Murthy Peter Teriete University of California, USA Sanford-Burnham Institute for Medical Research, USA Nico P E Vermeulen VU University Amsterdam, Netherlands Session Introduction Title: In vivo delivery of transcription factors with chemically modified oligonucleotides Niren Murthy, University of California, USA Title: Eradication of asbestos tumors in vivo with histone deacetylase inhibitors-polymer conjugate nanoparticles for acid-responsive drug delivery Philippe Bertrand, Institut de Chimie des Milieux et Matériaux de Poitiers, France Title: The σ1 receptor as target for novel drugs Bernhard Wünsch, Westfalian Wilhelms-University of Münster, Germany Title: Using computer-aided drug design (CADD) techniques to optimize the natural product-derived phenylmethylidene-hydanto in scaffolds as promising antimetastatic leads Mudit Mudit, D'Youville College School of Pharmacy, USA Title: Design and development of small peptidomimetics of RXFP1 for the treatment of acute heart failure Akhter Hossain, University of Melbourne, Australia Title: Exploring pharmacological potential of Brazilian plants: SAM database - A tool for recording and comparison of molecules isolated from plants of the Brazilian semiarid Bruno Andrade, State University of Southwest Bahia, Brazil Title: Novel chemistry-based tools to study epigenetic enzymes in inflammation Frank J Dekker, Pharmaceutical Gene Modulation, The Netherlands Title: Current SAR on HIV: The flow from phenotypic assays via medicinal chemistry toin silico design Peter Teriete, Sanford-Burnham Institute for Medical Research, USA Title: Structure guided design and synthesis of SAR107375A, aselective and potent dual thrombinand factor Xa inhibitor Jerome Meneyrol, Sanofi-Aventis R&D, France Title: Molecular modeling approach to investigate the binding mode of 4-nerolidylcatechol into two subtypes of matrix metalloproteinases Kely Medeiros Turra, University of São Paulo, Brazil
MedChem & CADD-2014
Page 54 Niren Murthy, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
In vivo delivery of transcription factors with chemically modified oligonucleotides Niren Murthy University of California at Berkeley, USA
herapeutics based on transcription factors have the potential to revolutionize medicine, but have had limited medical Timpact because of delivery problems. In this presentation we demonstrate that a delivery vehicle, termed DARTs (DNA Assembled Recombinant Transcription factors), can for the first time deliver recombinant transcription factors in vivo, and rescue mice from acute liver failure. DARTs are composed of a double stranded oligonucleotide that contain a transcription factor binding sequence, and have hydrophobic C25 alkyl chains located at their 3’ ends, which are “masked” by acid cleavable galactose residues. DARTs have a unique molecular architecture, which allows them to complex transcription factors, target hepatocytes, disrupt endosomes, and release transcription factors into hepatocytes.We show here that DARTs can deliver the transcription factor Nrf2, to the liver, enhance the transcription of Nrf2 downstream genes, and protect mice from acetaminophen induced liver injury. The DART delivery strategy has tremendous therapeutic potential given the central role of transcription factors in biology and medicine.
Biography Niren Murthy is a professor in the Department of Bioengineering at the University of California at Berkeley. He received his PhD from the University of Washington in Seattle in Bioengineering in 2001, and then did postdoctoral research at U.C. Berkeley in Chemistry from 2001-2003. He started his academic career at Georgia Tech in 2003 and in 2012 moved back to U.C. Berkeley. His laboratory is an interdisciplinary laboratory that focuses on the development of new materials for drug delivery and molecular imaging. The Murthy laboratory has developed several new biomaterials and imaging agents, such as the maltodextrin based imaging agents, which are focused on improving the treatment and diagnosis of infectious diseases. In addition, the Murthy laboratory has developed numerous reagents for detecting radical oxidants, such as the hydrocyanines.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 55 Philippe Bertrand, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Eradication of asbestos tumors in vivo with histone deacetylase inhibitors-polymer conjugated nanoparticles for acid-responsive drug delivery Philippe Bertrand Institut de Chimie des Milieux et Matériaux de Poitiers, France
he study reports the synthesis of acid-responsive polymeric nanoparticles (NPs) consisting of polymer-histone deacetylase Tinhibitors conjugate. An innovative aspect lies in the NP conjugation mode of histone deacetylase (HDAC) inhibitors introduced with a clickable acid-responsive prodrug during monomer synthesis, prior to polymerization. The other novelty is due to the selected norbornene (NB)-polyethylene oxide (PEO) macromonomer allowing standardization of the polymerization process by Ring-Opening Metathesis Polymerization (ROMP) and functionalization through azide-alkyne click chemistry. It has been demonstrated that the synthesized polymer gave 300 nm core-shell spherical nanoparticles with low dispersity, high water dispersability thanks to the PEO shell and well controlled HDAC inhibitor prodrugs loading. Bioluminescence Resonance Energy Transfer (BRET) assay in living cells and viability experiments demonstrated efficient cellular internalization without additional chemistry, drug release inside cells with restoration of the HDAC inhibition and induction of apoptosis. Using combination of decitabine and our HDAC inhibitors functional NPs we were able to eradicate mesothelioma cancer cells in vivo.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 56 Bernhard Wünsch, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
σ The 1 receptor as target for novel drugs Bernhard Wünsch Westfalian Wilhelms-University of Münster, Germany
riginally the opioid receptor was subclassified into three subtypes, which were termed after their prototypical ligands Oµ (morphine), K (ketocyclazocine) and σ receptors (SKF-10, 047). However, this hypothesis was disproved, since the pharmacological effects of typical σ receptor drugs were not reversed by the opioid receptor antagonists naloxone and naltrexone. Finally, σ receptors were recognized as specific, non-opioid, non-PCP, but haloperidol-sensitive binding sites consisting of σ1 and σ2 subtypes. The two σ receptor subtypes can be differentiated by molecular weight, tissue distribution, and ligand binding profile. It has been shown that the σ1 receptor plays an important role in several socially relevant human diseases including schizophrenia, depression, Alzheimer’s disease, and drug/alcohol addiction. Antagonists at the σ1 receptor potentiate the pain-relieving effects of opioid analgesics and, moreover, can be used for the treatment of neurogenic pain. Due to their overexpression in several human tumor cell lines, σ1 and σ2 receptors are interesting targets for tumor therapy and diagnosis.
In the lecture the interactions of ligands with the binding site of the σ1 receptor are analyzed. The design and synthesis of novel
σ1 receptor ligands is presented. Spirocyclic piperidines and bridged piperazines represent very promising σ1 receptor ligands for further pharmacological evaluation. The development of a PET tracer for the imaging of 1σ receptors in the central nervous system is shown.
Biography Bernhard Wünsch has completed his PhD in 1987 from the University of Munich. After postdoctoral studies at the University of Berlin, he finished his habilitation in 1993. Then he moved to the University of Freiburg and finally to the University of Münster, where he is director of the Institute of Pharmaceutical and Medicinal Chemistry. He has been the dean of the faculty from 2005-2006. He is member of the collaborative research center 656 (Molecular Cardiovascular Imaging) and the Cluster of Excellence CiM (Cells in Motion). He has published more than 200 papers in reputed journals.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 57 Mudit Mudit, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Using Computer-Aided Drug Design (CADD) techniques to optimize the natural product-derived phenylmethylidene-hydanto in scaffolds as promising antimetastatic leads Mudit Mudit D'Youville College School of Pharmacy, USA
rostate and breast cancer is the second most prevalent cause of mortality in men and women, respectively. Approximately Pone-half of the current anticancer medications have been originally derived from natural products. Although a natural product can directly functionas a lead compound, considerable refinement in the natural product’s chemical scaffold is typically required to optimize the product’s pharmacodynamic factors. These factors include, but are not limited to, binding affinity, drug- likeness, cLogP, LogS, molecular weight, and an overall risk for toxicity. The optimization process accentuates the compound’s intrinsic potential to qualify as a lead candidate. Computer-aided drug design (CADD) techniques are widely used in natural product research to accelerate the process of overall drug design and discovery. This presentation will illustrate a proof-of- concept of this process using the example of 4 (hydroxyphenylmethylidene) hydantoin (PMH), (5Z)-5-(4-hydroxybenzylidene) imidazolidine-2, 4-dione. This chemical entity is a natural product isolated from the Red Sea sponge Hemimycale Arabica. This product has demonstrated antimetastatic activity in a number of in vitro/ in vivo models of prostate and breast cancer. Based on the natural product inspired scaffold, several related analogs of PMHs were synthesized to improve the antimetastatic activity. This talk will present the various CADD techniques that were usedto optimize PMH activity. This optimization resulted in severalfold-improvementin the in vitro/in vivo antimetastatic properties. This presentation will underscore the importance of computer-aided design in natural product research and its application in improving the efficiency of the drug discovery and development process.
Biography Mudit Mudit joined D'Youville College as an Assistant Professor in the School of Pharmacy’s Department of Pharmaceutical, Social and Administrative Sciences in Fall 2010. He earned his PhD in Pharmaceutical Sciences from the University of Louisiana at Monroe (ULM). He is an active member of several professional organizations including the American Association of Colleges of Pharmacy (AACP), American Association of Pharmaceutical Scientists (AAPS), American Chemical Society (ACS), and Kappa Psi Pharmaceutical Fraternity. He has given numerous research presentations both at regional and national meetings, and has been recognized by the AAPS for excellence in graduate education in the fields of Drug Design and Discovery (DDD).
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 58 M Akhter Hossain, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Design and development of small peptidomimetics of RXFP1 for the treatment of acute heart failure M Akhter Hossain University of Melbourne, Australia
eart disease is the second biggest killer. Human relaxin 2 (H2 relaxin), an insulin-like peptide, passed a phase III clinical Htrial (in 2012) for its vasodilatory benefits in patients with acute heart failure and serelaxin (recombinant H2 relaxin) was recently (in 2013) granted a “breakthrough therapy” designation by the FDA. The author’s group aims to improve this current drug and develop the next generation molecule. In order to maximize its future translational potential, the group will address the three following issues: 1. Large size and complex structure: The size (53 amino acids) and complex structure (two chains, linked by three disulfide bonds) of H2 relaxin represent a considerable challenge for its synthesis limiting modifications of the peptide to optimize its efficacy and stability. 2. Cross-reactivity with other receptors: H2 relaxin exerts its biological actions through its cognate receptor, Relaxin Family Peptide Receptor 1 (RXFP1; initially discovered as LGR7). However, it also activates RXFP2, the native receptor for the related insulin-like peptide 3, INSL3; opening the possibility of potential side-effects through RXFP2-mediated physiological processes. 3. Short half-life in blood: Like insulin, H2 relaxin has a very short half-life. Hence, when injected into patients, H2 relaxin will lose half its activity within 10 minutes because it is degraded by blood enzymes and cleared by the kidney and liver. Thus, there is an urgent need to design and develop simpler H2 relaxin analogues that are easier to prepare and modify, have high selectivity for RXFP1 and retain their activity for an extended therapeutic time-frame in patients with acute heart failure.
Biography M Akhter Hossain has completed his PhD at the age of 27 years from Tokyo Institute of Technology and Postdoctoral studies from The University of Melbourne. He is the Head of insulin peptides laboratory at Florey Institutes of Neuroscience and Mental Health, The University of Melbourne, Australia. He has published more than 70 papers in reputed journals including in JACS, PNAS, JMedChem and JBC. He is serving as an editorial board member of two journals including Frontiers in Chemical Biology. His group is interested in therapeutic insulin-like peptide-based drug design and development.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 59 Bruno Andrade, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Exploring pharmacological potential of Brazilian plants: SAM database - A tool for recording and comparison of molecules isolated from plants of the Brazilian semiarid Bruno Andrade State University of Southwest Bahia, Brazil
atabases of molecules have become a great tool for scientists and researchers working in drug development because Dthey provide information of various types of molecules, which becomes crucial when trying to find a structure with pharmaceutical activity. Several plants of semi-arid of Bahia, Brazil, have been studied in recent years in an attempt to find new therapeutic targets for a variety of pathologies. However, despite several efforts our knowledge is still very small about its mechanism of action of these natural compounds. Then, we developed a database which allow the storage of information and comparison of molecules isolated from plants of Brazilian semiarid region, because of its great diversity of plant species, and compounds that can be useful for applied drug development against human diseases. Some of the functionalities of this tool include recording molecule structures, using SMILES code, evaluation of similarity between molecule structures (including Tanimoto coefficient), comparison of molecules with external databases like ChEMBL and ZInc., as well as the calculation of chemical proprieties such as molecular weight, HbA, HbD and ClogP that satisfy or not the Lipinski’s rule. The construction of this database is based on Java technology used for the internet and intranet. Some features, such as creating the structure of molecules, calculating the similarity between molecules and MOL files generation were obtained from the Open Source library Indigo, developed by GGA Software Services. The generated data is stored in a relational database, used as System Manager Database (DBMS) MySQL Server 5.5.28.
Biography Bruno Andrade has completed his PhD from the State University of Feira de Santana, Brazil, in 2011. He has experience in Biotechnology with emphasis on structural and functional analysis molecules isolated from microorganisms, animals and plants with pharmacological potential, and working on the following topics: Homology Molecular Modeling, Docking and Virtual Screening. He is currently adjunct professor at the State University of Southwest Bahia, Brazil, School of Medicine. He has published over 25 works (including 6 papers) in reputed journals and international meetings.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 60 Frank J Dekker et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Novel chemistry-based tools to study epigenetic enzymes in inflammation Frank J Dekker, Maria-Eleni Ourailidou and Thea van den Bosch Pharmaceutical Gene Modulation, The Netherlands
hronic inflammatory diseases, such as, for example, asthma, afflict millions of people worldwide. In such diseases enzymes Care crucial regulators and therefore represent potential drug targets. Nevertheless, the activities of these enzymes are poorly studied due to a lack of convenient tools for modulation and detection. To address this problem further, we are developing novel detection methods and small molecule inhibitors to study signal transduction pathways that are involved in inflammation. Our studies focus on protein acetylations at lysine residues, which have a versatile regulatory role in signal transduction pathways. Among others lysine acetylations, are key regulators of the histone code in epigenetic regulation of gene transcription. We are developing a novel strategy to study protein acylation using metabolic labelling with alkenylated short fatty acids, which can be detected by bioorthogonal ligation of detection labels using the oxidative Heck reaction. This strategy enables the identification of novel protein acylations sites. The novel ligation method proved to be a robust replacement for the frequently used alkyne labelling in combination with the ‘click reaction’. In addition, mass spectrometry analysis was utilized to quantify endogenous protein lysine acetylations. Interestingly, this method also enabled the identification of cross-talk of lysine acetylation with other posttranslational modifications in signal transduction pathways.
Biography Frank J Dekker has completed his PhD at the age of 26 years from Utrecht University, The Netherlands, and he did postdoctoral studies at the Max-Planck Institute for molecular physiology in Dortmund, Germany. He is now an Associate Professor in Chemical Biology at the University of Groningen, The Netherlands. He has published more than 40 papers in reputed journals and received prestigious research grants from national funding agencies and the European research council (ERC).
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 61 Peter Teriete, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Current SAR on HIV: The flow from phenotypic assays via medicinal chemistry toin silico design Peter Teriete Sanford-Burnham Institute for Medical Research, USA
ellular phenotypic assays provide a powerful method to investigate the capability of small molecules to perturb important Cbiological processes. A small library of dihydropyrimidinone (DHPM) derivatives prepared using continuous flow chemistry was tested in phenotypic assays and provided a hit that inhibited the replication of the human immunodeficiency virus (HIV) in cells. Investigation of the structure activity relationships (SAR) around this compound using flow synthesis methodology to rapidly and efficiently generate analogues led to the identification of potent HIV replication inhibitors with promising drug-like properties. Importantly, some of the lead structures inhibit the replication of a drug resistant strain of HIV. Mechanistic studies coupled with 3D in silico modeling suggest that these compounds exert their effects by inhibiting the viral RT enzyme.
Biography Peter Teriete completed his DPhil in biophysics from the University of Oxford, UK and completed postdoctoral studies at the Sanford-Burnham Institute for Medical Research, La Jolla, CA. As a project manager there, he utilizes his extensive expertise in structural biochemistry and biophysical characterization in the design and development of novel small molecule inhibitors of HIV as well as many other pathologies.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 62 Jerome Meneyrol et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Structure guided design and synthesis of SAR107375A, aselective and potent dual thrombin and factor Xa inhibitor Jerome Meneyrol1, Markus Follmann2, Gilbert Lassalle1, Volkmar Wehn2, Guillaume Barre1, Tristan Rousseaux1, Jean-Michel Altenburger1, Frederic Petit1, Zsolt Bocskei1, Herman Schreuder2, Nathalie Alet1, Jean-Pascal Herault1, Laurence Millet1, Frederique Dol1, Christan Hasbrand2, Paul Schaeffer1, Freddy Sadoun1, Sylvie Klieber1, Christophe Briot1, Françoise Bono1 and Jean-Marc Herbert1 1Sanofi-Aventis R&D, France 2Sanofi-Aventis R&D, Germany
ral treatment through direct inhibition of the main serine proteases of the coagulation cascade appears one of the Omost promising strategies to substitute anti-vitamin K long term treatment in the field of cardiovascular diseases. In that particular context, SAR107375 is a novel oral and intravenous anticoagulant, inhibiting both factors Xa and thrombin activities. Despite important efforts in various research laboratories, it remained very challenging to identify dual inhibitors of these two key enzymes of the coagulation cascade with sufficient oral bioavailability in animals. SAR107375 resulted from a rational optimization process. Starting from compound with low factor Xa and modest anti-thrombin inhibitory activities (IC50’s of 3.5 and 0.39 μM, respectively), structure-based optimization of a neutral P1 fragment and fine tuning of P2 and P3− P4 residues considerably allowed improvements of both activities.Indeed, during the course of this chemical optimization, we solved a number of thrombin and factor Xa crystal structures in complex with inhibitors and the main guiding principles will be illustrated in order to obtain dual inhibition through the detailed analysis of those complexes. The discovery of development candidate SAR107375 may help to demonstrate the expected beneficial effects in patients from combining inhibition of both factor Xa and thrombin in one single molecule. Biography Jerome Meneyrol has completed his PhD at the age of 27 years from Paris 5 University and postdoctoral studies from Newcastle University. He is the Associate Director of Medicinal Chemistry for Early to Candidate (E2C), a Sanofi R&D organization. He has published 5 papers in reputed journals and 1 patent. Moreover, he has contributed to the identification of 2 preclinical candidates in the thrombosis and cancer fields.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 63 Kely Medeiros Turra et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Molecular modeling approach to investigate the binding mode of 4-nerolidylcatechol into two subtypes of matrix metalloproteinases Kely Medeiros Turra1, Silvia Berlanga de Moraes Barros1 and Kerly Fernanda Mesquita Pasqualoto2 1University of São Paulo, Brazil 2Butantan Institute, Brazil
atrix metalloproteinases (MMP) are proteinases involved in the extracellular matrix degradation. MMP-2 and MMP-9 Msubtypes are over expressed in several human cancer types becoming attractive targets to develop novel anticancer agents. A metabolite from the plant Pothomorphe umbellata, named 4-nerolidylcatechol (4-NC), has showed the ability to inhibit both MMP in vitro and in vivo. In this regard, molecular docking (Autodock software) and molecular dynamics simulations (MDS; MOLSIM 3.2 program) were performed in order to investigate the binding mode of 4-NC into MMP-2 and MMP-9. Autodock was used to explore the best binding interactions of 4-NC in the active site of each enzyme. The grid box included the entire binding site of each enzyme and a grid spacing of 0.375 Å was set up (AutoGrid). The zinc ions were parameterized as zinc radius (1.48) and well depth (0.550). Thirty docking runs were performed for each complex. The best binding model was chosen regarding the energy rank position and orientation of ligand in the active site. The best complexes from docking approach were energy-minimized and employed as initial structures to perform a short warming-up MDS sampling scheme and, then, a longer simulation (5 ns) at 310 K. The ligand 4-NC was oriented in the catalytic site by accommodating its side chain in an adjacent pocket (S1’) to the catalytic site. The hydroxyl groups were near the zinc atom allowing the coordination. The size of S1' pocket has provided changes in the binding mode of 4-NC in MMP-2 and MMP-9.
Biography Kely Medeiros Turra is a PhD student at the age of 29 years from University of São Paulo. She works in the computer-aided drug design field, applying molecular modeling and QSAR approaches to develop novel metalloproteinases inhibitors as antitumor agents against melanoma.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 64 244th OMICS Group Conference 3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Scientific Tracks & Abstracts (Day 3)
MedChem & CADD-2014 Page 66 Track 11 Day 3 December 10, 2014 11: Membrane Proteins as Pharmaceutical Targets Session Chair Session Co-Chair Victor J Hruby Pierre Falson University of Arizona, USA IBCP, France Session Introduction Title: Tracking anti-tumor drugs: Ruthenium(II)-cyclopentadienylcomplexes as promising agents M Helena Garcia, Universidade de Lisboa, Portugal Title: TAAR1 ligands as prospective neuroleptics: From D-neuron study Keiko Ikemoto, Iwaki Kyoritsu General Hospital, Japan Title: Small-molecule modulators of thiamine transport in pathogenic bacteria Anna K H Hirsch, University of Groningen, The Netherlands Title: The behavior of detergents around membrane proteins is more complex than supposed, as revealed by a new method of quantitation Pierre Falson, IBCP, France Title: Design of multivalent ligand for the detection and treatment of disease Victor J Hruby, University of Arizona, USA Title: Polymer ‘ruthenium-cyclopentadienyl’ conjugates: A new approach to fight cancer Andreia Valente, Universidade de Lisboa, Portugal
MedChem & CADD-2014
Page 67 M Helena Garcia et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Tracking anti-tumor drugs: Ruthenium(II)-cyclopentadienyl complexes as promising agents M Helena Garcia, Tânia S Morais, Andreia Valente and Fernanda Marques Universidade de Lisboa, Portugal
uthenium complexes hold great potential as alternatives in cancer treatment and have been the most widely studied non- platinum anticancer drug candidate. During the recent years our group has been involved in the synthesis of new half R η5 sandwich “Ru( -C5H5)” derived compounds, of which cytotoxicity was found, in most of the cases, better than that of cisplatin against several cancer cell lines of typically low, medium and high resistance to metallodrugs, namely ovarian, breast, colon and prostate human tumors (A2780, MCF7, MDAMB231, HT29 and PC3 cell lines). The therapeutic effect of one of these compounds was evaluated in an orthotopic triple negative breast cancer (TNBC) mouse model and has demonstrated the in vivo capacity to suppress tumor growth, not presenting the severe side-effects of other non-targeted chemotherapeutic agents. Moreover, autopsy of the animals did not show any metastasis in the lungs or other organs. In this presentation, we present an overview of our most recent progress in this field, highlighting our chief results. Thus, a new generation of η5 compounds will be presented, based in the fragment “Ru( -C5H5)”with appended molecules, in order to optimize our best results already obtained, having also in view the recognition by cancer cells, for target therapy. Finally, studies to understand the pharmacokinetic and the involved mechanisms of action will also be presented.
Biography M Helena Garcia is Associate Professor with “Habilitation” at University of Lisbon. Her scientific areas of research have been mainly centered in synthesis of organometallic compounds in view to potential applications with benefit to the society. She has authored over eighty publications and several book chapters. She has been leader of several national and European funded scientific research projects and is Member of the “Division of Organometallic Chemistry” of European Association for Chemical and Molecular Sciences, as delegate of Portuguese Chemical Society, since 1992. She is Coordinator of the International Office at Faculty of Sciences, University of Lisbon.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 68 Keiko Ikemoto, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
TAAR1 ligands as prospective neuroleptics: From D-neuron study Keiko Ikemoto Iwaki Kyoritsu General Hospital, Japan
ecent pharmacological studies have shown the importance of trace amine-associated receptor, type 1(TAAR1), a subtype Rof trace amine receptors, as a prospective target receptor for novel neuroleptics. Endogenous ligand producing neuron of TAAR1 is the D-neuron, i.e., trace amine neuron, defined as “the aromatic L-amino acid decarboxylase neuron, neither contains dopamine (DA) nor serotonin”. We found significant decrease of D-neurons (trace amine neurons) in the nucleus accumbens (Acc) of autopsy brains of patients with schizophrenia. Animal model studies have shown that reduced stimulation of TAAR1 on DA neurons in the midbrain ventral tegmental area (VTA) increased firing frequency of VTA DA neurons. Thus, D-neuron reduction and consequent trace amine decrease, causing TAAR1 stimulation reduction on terminals of midbrain VTA DA neurons has been shown as the molecular basis of mesolimbic DA hyperactivity of schizophrenia. D-neuron decrease in Acc of postmortem brains is supposed be due to neural stem cell (NSC) dysfunction in the subventricular zone of lateral ventricle (cf. NSC dysfunction hypothesis of schizophrenia).The new “trace amine hypothesis” (“D-cell hypothesis”), of schizophrenia in which D-neuron and TAAR1 is involved, is in agreement with recent reports showing effectiveness of TAAR1 ligands for schizophrenia model animals. This hypothesis links DA hypothesis of schizophrenia with NSC dysfunction hypothesis. D-neuron reduction in the Acc, an anatomical area known for an antipsychotic acting site, would let us assume TAAR1 ligand searching study being pivotal in novel neuroleptics discovery.
Biography Keiko Ikemoto, MD, PhD, graduated Shiga University of Medical Science in 1985, specialized in Psychiatry and Neuroscience. She studied monoamine neuronal system and sleep as Boursiere du Gouvernement Francais in the Department of Experimental Medicine, Claude Bernard University (1995-1996). She continued research in Department of Anatomy, Fujita Health University, Hanamaki National Hospital, Fukushima Medical University, School of Medicine, Shiga University of Medical Science, and Iwaki Kyoritsu General Hospital, in Japan. She organized the 1st Symposium for Brain Bank, in Fukushima in 2006. Now she chairs the Department of Psychiatry, Iwaki Kyoritsu General Hospital, Japan.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 69 Anna K H Hirsch, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Small-molecule modulators of thiamine transport in pathogenic bacteria Anna K H Hirsch University of Groningen, The Netherlands
nergy coupling factor (ECF) transporters are a class of ATP-binding cassette (ABC) transporters that mediate the uptake of Evitamins in prokaryotes. They consist of an energizing module and a substrate-binding protein (S-component). Different S components can interact with the same energizing module.1.ThiT is the thiamine-specific S-component.2. Based on the cocrystal structure of ThiT-thiamine (1).3 we have designed and synthesized thiamine analogues to identify which residues are the key for substrate binding and to elucidate the mechanism of transport.
Biography Anna K H Hirsch read Natural Sciences at the University of Cambridge and spent her third year at the Massachusetts Institute of Technology. Her Master’s project focused on the double conjugate addition of dithiols to propargylic carbonyls under the supervision of Prof. S. V. Ley. She received her PhD in 2008 from the ETH Zurich working on the design and synthesis of the first inhibitors for the kinase IspE under the supervision of Prof. F. Diederich. Subsequently, she joined the group of Prof. Jean-Marie Lehn at ISIS (Strasbourg). Her research interests focus on rational approaches to drug design.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 70 Pierre Falson et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
The behavior of detergents around membrane proteins is more complex than supposed, as revealed by a new method of quantitation Pierre Falson, Vincent Chaptal, Arnaud Kilburg and Frédéric Delolme IBCP, France
embrane proteins (MPs) represent more than 60% of pharmaceutical targets for which different approaches require Mto maintain them in aqueous solution in a native state, e.g., crystallography, ligand screening, antibody production, immunization and other applications. Such solution state is essentially obtained by using detergents. They are amphipathic molecules which compete with lipid and disrupt biological membranes in which MPs are embedded. Detergents replace lipids around hydrophobic patches of MPs, thereby keeping them in solution and preventing their aggregation during the process from extraction to purification.A key information when MPs are extracted and maintained in a soluble detergent-MP complex is to know the true concentration of detergent present in the medium, largely dependent on the membrane protein of interest and directly influencing the level of aggregation, topology, crystal growth and stability. Unless using radiolabelled compounds, there is no method to get this information routinely, quickly and with any detergent. A method providing such information potentially for any detergent, quickly and with a high degree of accuracy have been set up. The method based on the determination by MALDI MS of the ratio of deuterated/protonated detergents or that of structurally close molecules when a deuterated version is not available. The method was validated withfoscholine 12 (FC12), dodecylmaltoside (DDM), octylglucoside (OG), maltose neopentyl glycol (MNG), Calix[4]arene-based detergents (C4Cn), CHAPS and cholate, by measuring their concentrations in different extraction conditions/purification, concentration by ultrafiltration, dialysis and gel filtration of various membrane proteins. The amount of detergent associated with a variety of membrane proteins with different topologies, membrane spanning domains, functions and oligomerization states (ABC transporters, GPCR, ADP/ATP exchanger, proteins fromprokaryotic efflux systems) showing detergent:MP ratio ranging from 130 to 700mol/mol depending of the MP and the detergent, could be measured. Finally, an extra amount of detergent released after ultrafiltration followed by gel filtration revealing that MPs are not simply embedded in a detergent micelle but rather sequester twice more detergent to protect their hydrophobic area through a gradient from tight to weak interactions were detected.
Biography Pierre Falson got his PhD at the LYON University. He is a CNRS (National Centre for Scientific Research) Research Director, enzymologist and membrane proteins biochemist, co-leading the Drug resistance mechanism and modulation team in the BMSSI CNRS-UCBL1 Research Unit. PFhas published 54 publications, patented 6 inventions and licensed2 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 theCNRS.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 71 Victor J Hruby, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Design of multivalent ligand for the detection and treatment of disease Victor J Hruby University of Arizona, USA
any of our most prevalent degenerative diseases such as cancer, diabetes, prolonged and neuropathic pain etc. results Mfrom multiple changes in our expressed genome. We and others have suggested that for the detection and treatment of these diseases multivalent ligands can provide distinct advantages over monovalent drugs that are the mainstay of most current therapies. Advantages such as enhanced efficacy and synergy and reduction in toxicities can be expected. The design of such ligands requires careful consideration of the three dimensional organization of the multiple pharmacophores so that they can independently, and without interference, interact with their particular receptor/acceptor target and retain their individual binding affinities and efficacies at each target. Peptides are ideally suited for this purpose. This approach with two different examples that require different design strategies will be illustrated. In the first case we will design multivalent ligands that have adjacent, spacer, separated or overlapping pharmacophores and agonist and antagonist activities for the different pharmacophores for the treatment of prolonged and neuropathic pain but without the development of tolerance, addiction, or other toxic side effect of current clinical drugs for prolonged and neuropathic pain. In the second example we will develop novel scaffolds for the design of hetero- and homo- valent ligands for the detection and treatment of cancer. In this approach the pharmacophores must be arranged in 3D space so that they cross-link receptors/acceptors on the cell surface. The synergies obtained can be substantial (102 to 103). It will also be demonstrated that tremendous kinetic advantages can be obtain for cancer detection using this approach.
Biography Regents Professor Victor J. Hruby received his PhD from Cornell University and did his Postdoctoral Studies at Cornell University Medical Center with Nobel Laureate Vincent du Vigneaud. Currently, he is a Regents Professor at the University of Arizona with appointments in four other departments and programs. He has over 1, 200 publications, serves on the editorial boards of numerous journals, and has been a member of several NIH Study Sections. His major research interests are in the chemical biology, conformation-bioactivity relationships, drug design, molecular mechanisms of information transduction of peptide hormones and neurotransmitters and their ligands that modulate health and disease. He has won numerous awards for his accomplishments including most recently the ACS Ralph F. Hirschmann Award, the ACS Arthur C. Cope Scholar Award, and the APS Murray Goodman Award.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 72 Andreia Valente et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Polymer ‘ruthenium-cyclopentadienyl’ conjugates: A new approach to fight cancer Andreia Valente1, M Helena Garcia1, Leonor Côrte-Real1, Guilherme Nogueira1, Philippe Zinck2, António Matos1, 3 and Fernanda Marques1 1Universidade de Lisboa, Portugal 2UCCS, France 3CiiEM - Centro de Investigação Interdisciplinar Egas Moniz, Portugal
he continuous rising of cancer patients’ death rate undoubtedly shows the pressure to find more potent and efficient Tdrugs than those in clinical use, mainly based in platinum. These agents only treat a narrow range of cancer conditions with limited success and are associated with serious side effects caused by the lack of selectivity. The ideal situation is to have a drug that is only delivered to the tumor without affecting the healthy tissues. In this frame, our research group has recently published the synthesis and preliminary biological activity against several cancer lines of a new high molecular weight ruthenium-polymer complex.This conjugate incorporates a tumor-specific molecule attached to the polymeric chain and a cytotoxic fragment based on the “Ru-cyclopentadienyl” core, which presents high cytotoxic activity in several human cancer cell lines. The important potential of this family of polymer-ruthenium conjugates has been also revealed by studies of cellular uptake, molecular targets determination and pH-dependent release of the cytotoxic moiety. Our approach is different of those already reported in the literature, and we expect that it will lead to different reactivity patterns and thus a different model of behavior. Within the present presentation we will unveil possible targets and mechanism of action of this new family of ruthenium-polymer conjugates.
Biography Andreia Valente completed her PhD in 2010 from the Université de Lille I (France) on the field of Polymerization Catalysis. Then, she joined the Organometallic Group at Faculty of Sciences, University of Lisbon (Portugal) where she got a first post-doc position in synthesis of organometallic compounds for nonlinear optic applications, followed by a second post-doc in the field of medicinal inorganic chemistry. She is presently a researcher (academic) at the same Institution, directing now her efforts to the synthesis of new polymer-metal complexes as targeted drug-delivery systems in view to cancer therapy.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 73 Track 12 Day 3 December 10, 2014 12: Recent Research and Developments Session Chair Session Co-Chair Jetze J Tepe Bin Xu Michigan State University, USA Virginia Tech, USA Session Introduction Title: Design of mechanistically distinct proteasome inhibitors for the treatment of multiple myeloma Jetze J Tepe, Michigan State University, USA Title: Molecular characterization and design of a key new hormone, irisin Bin Xu, Virginia Tech, USA Title: Structure-based discovery of new modulators targeting nuclear X receptor alpha for cancer therapy Ying Su, Sanford-Burnham Medical Research Institute, USA Title: Privileged heterocycles by palladium-catalyzed aerobic oxidative isocyanide insertion Romano V A Orru, VU University Amsterdam, The Netherlands Title: Visual binding: A radically new concept to support the medicinal chemist’s quest for innovative NMEs Carsten Detering, BioSolve IT Inc., USA Title: A G-quadruplex/i-motif switch in the HRAS promoter as target for anthrathiophenediones that show a strong anti-proliferative activity in urinary bladder cancer cells Luigi E Xodo, University of Udine, Italy Title: Multi-target approach to anti-inflammatory drugs -in silico and medicinal chemistry Eugen Proschak, Goethe-University of Frankfurt, Germany Title: Identification and optimization of tertiary sulfonamides as RORc inverse agonists Benjamin P Fauber, Genentech, Inc., USA Title: Massive changes to the biophysical properties of DNA upon binding antiviral polyamides Gaofei He, University of Missouri-St. Louis, USA Title: The communion of medicinal chemistry and nanotechnology in anticancer therapeutics Debatosh Majumdar, Glycosyn LLC., USA Title: Evaluation of Satureja hortensis leaves essential oil pharmacological activities A P Manjikyan, Yerevan State Medical University, Armenia Title: Phytochemicals and antioxidant capacities from fruits Prasad K N, Monash University Malaysia, Malaysia Title: Selection and characterization of RNA aptamers targeting the genomic 5’-UTR in the dengue virus Adriana Freitas Neves, Universidade Federal de Goiás, Brazil Title: SurR9C84A exhibits cardioprotective effects against melphalan induced cardiotoxicityin primary human cardiomyocytes Ajay Ashok, Deakin University School of Medicine, Australia
MedChem & CADD-2014
Page 74 Jetze J Tepe, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Design of mechanistically distinct proteasome inhibitors for the treatment of multiple myeloma Jetze J Tepe Michigan State University, USA
ultiple myeloma (MM) is anincurable and fatal type of cancer that affects plasma cells, which will accumulate in the bone Mmarrow leading to bone destruction. Although the leading MM drug, bortezomib, is undoubtedly one of the biggest breakthroughs in this field, nearly all patients become intolerant or resistant within a few years, after which the average survival time is less than one year. 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. Considering that these agents interact with the proteasome via a non-competitive mechanism they act 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. This presentation will discuss thesynthesis and biological properties in cell culture and in vivo of this alternative way of regulating the human proteasome.
Biography Jetze J Tepe received his PhD 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.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 75 Bin Xu, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Molecular characterization and design of a key new hormone, irisin Bin Xu Virginia Tech, USA
xercise has well-recognized beneficial effects on system metabolism. Irisin was recentlyidentified as an exercise-induced Epeptide hormone secreted by skeletal muscle in mice andhumans. The hormone is thought to bind to so far unidentified surface receptor on white fat cellsand induces “browning” effects that improve the tissue metabolic profile and increase wholebodyenergy expenditure. As a potential new anti-obesity and anti-diabetes target, this peptidehormone is however poorly characterized. We have successfully manufactured recombinant irisin, which provides a key reagent for detailed biochemical, biophysical, and pharmacologicalcharacterizations. Wild type irisin exists in the form of dimer in solution. Through structurebasedcomputational modelling and systematic surface mutagenesis, we have mapped out the detailed dimeric interface and engineered monomeric irisin variants. Successful manufacture of astable, monomeric, active irisin provides a novel biological for the treatment of obesity and type2 diabetes. Furthermore, we discovered a novel biological function of irisin towards pancreatic β-cells, an effect has not been reported so far. Putative membrane receptor for this hormone waslocalized to the cell surface membrane of both β-cells and adipocytes. Using a novelphotoaffinity crossing approach, we are actively pursuing to identify the cell surface membranereceptor through which the hormone functions. Our work provided an excellent example of theutility of structure-based and computer aided design for novel protein therapeutic targets.
Biography Bin Xu received his PhD from Case Western Reserve University in 2004, followed by postdoctoral studies at Fred Hutchinson Cancer Research Center. Since 2011, he has been atenure-track Assistant Professor in the Department of Biochemistry and Center for Drug Discovery at Virginia Tech. His research interests concern cell surface receptor-ligand binding, signalling, novel receptor discovery, and translational structure-based and computer-aided liganddesign with applications to novel peptide hormone-receptor recognition, nutrient-sensing GPCRs, and immunoreceptors - viral ligands host-pathogen interactions relevant to diabetes, obesity, and infectious diseases. He has published more than two dozen publications in premierinternational peer-reviewed journals.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 76 Ying Su, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Structure-based discovery of new modulators targeting nuclear X receptor alpha for cancer therapy Ying Su Sanford-Burnham Medical Research Institute, USA
etinoid X receptor-alpha (RXRα) is implicated in the regulation of many biological processes and also represents a unique Rintracellular target for pharmacologic interventions. Efforts on discovery of small molecules targeting RXRα have been primarily focused on the molecules that bind to its classical ligand-binding pocket (LBP). Using structure-based approach and in collaboration with a multi-disciplinary team, we have identified novel RXRα modulators that use new binding mechanisms to mediate the biological functions of RXRα. The new compounds can effectively suppress AKT activation and promotes apoptosis of cancer cells in a RXRα-dependent manner by inhibiting the interaction between a truncated RXRα and the p85α subunit of PI3K.
Biography Ying Su, PhD, is computational chemist with over 15 years of experience on computer-aided drug design. She received her PhD from the University of California, San Diego. After a postdoctoral appointment at the Scripps Research Institute, she worked for several local biotech companies. She joined the Sanford-Burnham Medical Research Institute in 2005 to build and lead a HTS informatics and Cheminformticsgroup. She is co-author of over 40 peer-reviewed scientific publications.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 77 Romano V A Orru, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Privileged heterocycles by palladium-catalyzed aerobic oxidative isocyanide insertion Romano V A Orru VU University Amsterdam, The Netherlands
socyanides have been important building blocks in organic synthesis since the discovery of the Ugi reaction and related Iisocyanide-based multicomponent reactions. In the past decade isocyanides have found a new application as versatile C1 building block in palladium catalysis. We considerably contributed to the development of novel atom- and step efficient Pd- catalyzed reactions involving isocyanide insertion in the last couple of years. The author believes these reactions offer a vast potential for the synthesis of nitrogen containing fine chemicals. In this context, the author and his team recently developed a novel palladium-catalyzed aerobic oxidation reaction that produces guanidine-containing and related heterocycles from bisnucleophiles and aliphatic isocyanides. The reaction is applicable to a wide variety of pharmaceutically relevant heterocyclic systems, as illustrated by a formal synthesis of astemizole and norastemizole. Easily handled and relatively low-cost Pd(OAc)2 is used as the catalyst without an additional ligand or base and molecular oxygen-the most sustainable oxidant available— as the oxidant. The procedure is operationally simple, since bench solvents and atmospheric pressure are used, and environmentally benign due to the low catalyst loading, renewable solvent and high atom efficiency. In this presentation the author will discuss this new reaction in relation to the quickly developing field and our other contributions in this area.
Biography Romano V A Orru holds currently the postion of Chair of Synthetic & Bio-organic Chemistry of the VU-University in Amsterdam. In the past five years he received several major research grants from local, national and international funding agencies (e.g. NWO-CW TOP, EU-IMI). His main research interest focuses on sustainable synthetic method development employing cascade, domino (or tandem) processes. He is one of the leading players in the field of multicomponent, tandem and diversity oriented synthesis-related chemistry.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 78 Carsten Detering, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Visual binding: A radically new concept to support the medicinal chemist’s quest for innovative NMEs Carsten Detering BioSolve IT Inc., USA
he introduced next generation of binding affinity assessment tool Hyde, has been incorporated into a new software, TSeeSAR, which helps the medicinal chemist assess, modify and prioritize compounds within the context of the protein. Hyde has been completely revamped and shows another huge step forward to accurate compound scoring. After having optimized the protein-ligand complex, Hyde accounts for the hydrogen bond and desolvation energy of a ligand binding to a protein, effectively ruling out false positives by incorporating penalties for unmet interactions. Those penalties are visually communicated, giving intuitive clues where to improve the molecule with respect to binding affinity. An interactive editor helps making the necessary modifications, and the scientist gets immediate feedback whether those changes are leading into the right direction, i.e. if the binding affinity is getting better or not. The talk will highlight the science behind Hyde as well as case studies which demonstrate Hyde’s effectiveness.
Biography Carsten Detering obtained his PhD in Physical Chemistry from the Freie Universitaet Berlin in Germany in 2001. He did his Post Doc at the University of Washington in Seattle where he worked on the application of docking software for nucleic acid drug targets and rational design of new inhibitors for a malaria project. In 2005 he came to BioSolveIT in Germany as an Application Scientist first, later filling the position of Senior Key Account Manager and Executive VP of Sales, North America, before moving back to Seattle as CEO of BioSolveIT Inc., the north American subsidiary of BioSolveIT.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 79 Luigi E Xodo et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
A G-quadruplex/i-motif switch in the HRAS promoter as target for anthrathiophenediones that show a strong anti-proliferative activity in urinary bladder cancer cells Luigi E Xodo1, Susanna Cogoi1 and Andrey Shchekotikhin2 1University of Udine, Italy 2Academy of Medical Sciences, Russia
vidence that guanine repeats of genomic DNA are able to adopt non-canonical G-quadruplex structures is rapidly Egrowing, in particular since it was demonstrated that these unusual DNA structures occur in the cell. Recently, we have discovered that a G-quadruplex/I-motif switch in the HRAS promoter controls gene expression (a) and we thus designed small molecules that efficiently target the molecular switch. These quadruplex-binding ligands will open up a new approach in cancer therapy (a). In the present work we tested a number of antrathiophenediones with two alkyl side arms each bearing a terminal methylamino (2) or delocalized cationic guanidino (1) or chloroacetamidino (3-7) group. We discovered that the chloroacetamidines penetrate cancer cells more efficiently than non-cancer cells, and that they locate in the cytoplasm and nucleus. Among the analogs tested, compound 3, with two ethyl side chains, was found particularly bioactive in urinary bladder cancer cells, as it extinct the expression of oncogenic HRAS. We found that 3 stabilizes the G-quadruplex/I-motif switch and inhibits MAZ, a transcription factor that unfolds the switch and activates transcription. The extinction ofHRAS results in the blockade of the cell cycle in the G2/M phase and in suppression of cyclin D1. This brings the cells to apoptosis (PARP-1 cleavage, caspases 3/9 activation). The impact of compound 3 on pathways downstream of RAS was also analyzed.
Biography Luigi E Xodo had his degree in chemistry at the University of Trieste (Italy). He worked for a couple of years at the Universities of Reading and Surrey (UK) before being appointed Associate Professor at the University of Trieste. At present, he is full Professor of Biochemistry at the University of Udine (Italy). He published more than 90 papers in reputed journals.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 80 Eugen Proschak, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Multi-target approach to anti-inflammatory drugs - In silico and medicinal chemistry Eugen Proschak Goethe-University of Frankfurt, Germany
he “one drug - one target - one disease“paradigm in drug discovery has been reconsidered during the last decade. TThis paradigm change was mainly caused by high attrition rates in drug approvals due to toxicity and lack of efficacy. Dual or multi-target ligands have several advantages compared with selective compounds, including improved efficacy and more simple pharmacokinetic and pharmacodynamic properties in comparison to the combination of several drugs. Unfortunately, the rational design of polypharmacological compounds is a rather hard task and not well established. Previous studies established a synergistic inflammatory effect resulting from inhibition of 5-lipoxygenase (5-LO) or cyclooxygenases in combination with soluble epoxide hydrolase (sEH). In this study we apply different design strategies to yield dual 5-LO/ sEH inhibitors for treatment of inflammation. We present three methodic approaches to design dual inhibitors of 5-LO and sEH. In our first study, we connected previously pubished 5-LO and sEH pharmacophores, an imidazo-[1, 2a]-pyridine core with an aryl urea moiety via flexible propyl linker. The second study contains the discovery of a benzimidazole-based dual 5-LO/sEH inhibitor by means of in silico screening. The strategy of the virtual screening protocol was an exhaustive pairwise evaluation of pharmacophore models for both targets to obtain a dual-target pharmacophore model. Our last study deals with the development of a fragment based strategy for dual-target drug discovery. Here, we applied a modified self-organizing map algorithm for in silico recognition of molecular fragments binding both targets. The predicted properties were confirmed by complementary screening techniques: STD-NMR and enzyme assay. A variety of dual fragments active in both complementary assays could be obtained using self-organizing maps, which was optimized towards nanomolar inhibitory activity against both targets.
Biography Eugen Proschak has completed his PhD in 2008 from Goethe-University of Frankfurt. He is Junior Professor of Drug Design in Frankfurt and is leading an interdisciplinary research group. He has published more than 60 papers in reputed journals. His main research interest is design of multi-target drugs supported by in silico and fragment-based drug discovery.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 81 Benjamin P Fauber et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Identification and optimization of tertiary sulfonamides as RORc inverse agonists Benjamin P Fauber1, Olivier René1, Gladys de Leon Boenig1, Brenda Burton2, Yuzhong Deng1, Celiné Eidenschenk1, Christine Everett1, Alberto Gobbi1, Julie Hawkins2, Sarah G Hymowitz1, Adam R Johnson1, Hank La, MaryaLiimatta1, Peter Lockey2, Maxine Norman2, Wenjun Ouyang1, Weiru Wang1 and Harvey Wong1 1Genentech, Inc., USA 2Argenta, UK
creening a nuclear receptor compound subset in a RORc biochemical binding assay revealed a benzylic tertiary sulfonamide Shit. Using structure-based drug design principles, we created compounds with improved RORc biochemical inverse agonist activity and cellular potencies (<100 nM).These improved compounds also possessed appreciable selectivity for RORc over other nuclear receptors (>100-fold) and favorable physiochemical properties.
Biography Benjamin PFauber is a medicinal chemist at Genentech in South San Francisco, California. He earned his BSc from Colorado State University and PhD from the University of Texas at Austin. Prior to joining Genentech, he was employed by AstraZeneca and Array BioPharma as a medicinal chemist working in the areas of inflammatory disease and oncology.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 82 Gaofei He et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Massive changes to the biophysical properties of DNA upon binding antiviral polyamides Gaofei He1, James K Bashkin1, 2, Kevin J Koeller1, G Davis Harris1, Puhong Liao1, Cynthia M Dupureur1, Elena Vasilieva1, Carlos H Castaneda1, Maria J Scuderi1, Faten Tamimi1, Edith Fejer1, Shahrzad Hakami Kermani1, Chris Fisher and Terri G Edwards2 1University of Missouri-St. Louis, USA 2Nano Vir LLC., USA
-methyl-pyrrole and imidazole-derived polyamides (PAs), acting as DNA minor groove binders, are higher homologs of Nnatural products such as distamycin A. PAs show attractive biomedical properties and draw interest from many groups. A series of long hairpin polyamides was designed to target the high risk human papillomavirus types 16, 18 and 31, and shows antiviral activity in cell and tissue culture. With our designed PA library we found that large size (containing ≥14 rings, with a binding size ≥10 bp of DNA) was necessary for activity. Antiviral activities varied from highly active to complete inactive between the molecules with the same cognate DNA recognition properties. Antiviral activities also show little correlation to PA/DNA binding affinity. It has been since pursued the mechanism of action of antiviral polyamides, and polyamides in general with collaborators at NanoVir. It was mapped large regions of HPV16 and 18 genomes by DNase I and hydroxyl radical affinity cleavage with lead compounds (20% for HPV16 and 12% for HPV18). It was also investigated active PA- DNA-interactions via UV-Vis and Circular Dichroism. Active PAs show dramatically different thermodynamic and kinetic properties from commonly-used 6 to 8 ring PAs. Recently, for the purpose of biodistribution and metabolic stability studies, it was developed two independent synthetic routes for specific incorporation deuterium at one position. Stability studies of unlabeled compound were also carried out at several temperatures.
Biography Gaofei He completed his PhD from Carnegie Mellon University and his postdoctoral studies at University of Missouri-St. Louis, where he has recently begun teaching as well as conducting research. He has published more than 13 papers in reputed journals.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 83 Debatosh Majumdar, Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
The communion of medicinal chemistry and nanotechnology in anticancer therapeutics Debatosh Majumdar Glycosyn LLC., USA
ecent development in nanotechnology has an immense impact on the medicinal chemistry research. Nanomedicine is Ran interdisciplinary research field where medicinal chemistry, nanotechnology, and biology meet each other. We have combined medicinal chemistry and nanotechnology based approaches for cancer prevention, cancer therapy and development of new therapeutic agents. The flavonoid luteolin, 3’, 4’, 5, 7-tetrahydroxyflavone, is a natural antioxidant whichis usually found in its glycosylatedform in many green vegetables including broccoli, artichoke, celery, cabbage, cauliflower, green pepper, and spinach. Luteolin has a wide range of pharmacological properties ranging from anti-inflammation to anticancer effects. Luteolin has shown anticancer effects against lung cancer, head and neck cancer, breast, prostate, liver, colon, cervical, and skin cancer. We have synthesized water-soluble Nano-Luteolin from hydrophobic luteolin, and studied its anticancer activity against lung cancer and head and neck cancer. In vitro studies demonstrated that, both luteolin and nano-luteolin inhibited the growth of lung cancer cells (H292 cell line) and squamous cell carcinoma of head and neck (SCCHN) cells (Tu212 cell line). In Tu212 cells, the IC50value of luteolin was 6.96 μmol/L and that of nano-luteolin was 4.13 μmol/L. In H292 cells, the IC50 of luteolin was 15.56 μmol/L, and that of nano-luteolin was 14.96 μmol/L. In vivo studies using a tumor xenograft mouse model demonstrated that nano-luteolin significantly inhibited the tumor growth of SCCHN compared to theluteolin treated group. Furthermore, detail protein analysis of Nano-Luteolin treated SCCHN tumor of mice have shown a significant decrease of proliferative markers such as PCNA, E2F1, CDK4; and pro-survival factors such as phospho-prohibitin (pPHB), total PHB and Bcl2. However, under this condition pro-apoptotic factors such as Bax, cleaved caspase-9, and p53 have increased in Nano- Luteolin treated SCCHN tumor. In conclusion, our studies suggest that the Nano-Luteolin may be a potential therapeutic agent in the treatment of lung or, head and neck cancer.
Biography Debatosh Majumdar has completed his PhD in Organic Chemistry from the Complex Carbohydrate Research Center and the Department of Chemistry of the University of Georgia. He worked on the design and synthesis of biologically important carbohydrates and glycopeptides. He was a research fellow in the department of medicinal chemistry at the University of Michigan, where he worked on the design and synthesis of cysteine protease inhibitors. Then he worked on cancer therapy and cancer nanomedicine at the Emory Winship Cancer Institute of Emory University. Now he is a scientist at Glycosyn LLC., a premier biopharmaceutical company, where he is synthesizing biologically important carbohydrates, glycoproteins, and glycoconjugates. Hehas published many papers and book chapters, and has been serving as an editorial board member of the World Journal of Organic Chemistry, JSM Nanotechnology and Nanomedicine, and reviewers of PLos ONE, Frontiers in Bioscience, Drug Delivery Letters, and others.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 84 A P Manjikyan et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Evaluation of Satureja hortensis leaves essential oil pharmacological activities A P Manjikyan, M G Balasanyan and H V Topchyan Yerevan State Medical University, Armenia
atureja hortensis L. plant’s (Lamiaceae) pharmacological activities appears in a wide spectrum, due to their secondary Smetabolites and essential oils. The antimicrobial, antinociceptive and anti-inflammatory activities of Armenian flora Satureja hortensis L. leaves essential oil have been studied. The mentioned oil antinociceptive and anti-inflammatory activities have been estimated correspondingly in the tail-flick and xylene induced acute ears edema test of rats’ experimental model. The rats were pretreated with 20, 50 and 100 mg/kg doses. Essential oil antimicrobial effects preliminary qualitative comparable estimation was studied in a number of conditionally pathogenic microorganisms. The experiments were carried outin vitro in the petri plates using Mueller-Hinton media. The obtained results showed that the highest antinociceptive activity of the mentioned oil registered in the dose 50 mg/kg for 62.95% (p<0.001) and the anti-inflammatory activity is highly expressed in the dose 20 mg/kg, preventing edema for 50.45% (p<0.05). It was revealed that the essential oil has certain activity on E. coli, S. aureus, Bacillus sp., and fungi of Candida type. These results indicated thatSatureja hortensis L. leaves essential oil could serve as a potential source for development of new agents with analgesic, anti-inflammatory and antimicrobial activities.
Biography A P Manjikyan has graduated as Pharmacist in 2008 from Yerevan State Medical University. She is working in the Department of Pharmacy and doing PhD research under the supervision of Professor M G Balasanyan at YSMU, Armenia. Her research focuses on natural compounds anti-inflammatory and anti-nociceptive activities.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 85 Prasad K N et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Phytochemicals and antioxidant capacities from Dacryodes rostrata fruits Prasad K N1, Tee L H1, Ramanan R N1, Tey B T1, Chan E S1, Azrina A2, Amin I2, Yang Bao3 and Lau C Y3 1Monash University Malaysia, Malaysia 2Universiti Putra Malaysia, Malaysia 3Chinese Academy of Sciences, China
acryodes rostrata is an indigenous fruit found in Sarawak, Malaysia. The fruit is ovoid in shape, purple colour and rich Din oil, protein and minerals and used as food by the local communities. In this work, antioxidant components and antioxidant capacities of the extracts of peel, pulp and seeds of D. rostrata were evaluated. Total phenolic (1007±24 mg/g GAE DW) and flavonoid contents (2550±37 mg/g QE DW) of the seed extracts were higher when compared to peel and the pulp extracts. In addition, 1, 1-diphenyl-2-picryl hydrazyl (DPPH) free radical scavenging activity of the seed extracts were higher (65%), compared to peel (52%) and pulp (19%). Ferric reducing antioxidant power (FRAP) values of the seeds (1.22 mM FeSo4 equivalent) exhibited highest activity when, compared with peel (0.23 mM FeSo4 equivalent) and pulp (0.10 mM FeSo4 equivalent). Seed extract also showed highest total antioxidant capacity determined by phosphomolybdenum method. Liquid chromatography-mass spectra (LC-MS) of the seed extracts from D. rostrata revealed the presence of phytochemicals in the form of gallic acid, ellagic acid, epicatechin, kempferol and quercetin. Thus, D. rostrata seed extracts is having potent antioxidant capacity and could be used as a natural source of antioxidants.
Biography Prasad K N is a Senior Research Fellow at Chemical Engineering Discipline, School of Engineering, Monash University Malaysia. He obtained his PhD degree in Botany in India and worked as Post-Doctoral Researcher in China and in Malaysia. He has published over 50 international publications and 6 book chapters with h-index of 17. Currently, he has supervising Honours, Masters and PhD students. His research interest includes food chemistry, antioxidants, nutraceuticals, food processing and food composition.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 86 Adriana Freitas Neves et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
Selection and characterization of RNA aptamers targeting the genomic 5’-UTR in the dengue virus Adriana Freitas Neves1, Elismar de Jesus Nunes Cnossen1, Karina Marangoni2, Patrícia Thieme Fujimura2, Amanda Gabrielle da Silva1, Fabiana Souza Santos2, Jonny Yokosawa2, Carlos Ueira Vieira2 and Luiz Ricardo Goulart2, 3 1Universidade Federal de Goiás, Brazil 2Universidade Federal de Uberlandia, Brazil 3University of California Davis, USA
he increasing number of notifications of dengue infections is becoming a very important concern for global public Thealthcare programs. Combinatorial technologies aiming the selection of specific short conformational nucleic acid ligands against several biological targets, also known as aptamers, can be achieved by large-scale selections using the genomic SELEX technology. Our hypothesis is that aptamers can be selected directly against conformational structures that act as functional elements in the 5'-UTR sequence of dengue virus (DENV) RNA. These elements form RNA-RNA and protein-RNA interactions and play important roles in the virus RNA replication in the infected cell. Our aim was to select and characterize aptamers that bind to the 5’-UTR using the matrix-free SELEX method and in silico analyses. Products from the eighth selection cycle were isolated, cloned and sequenced. Nucleotide sequences from the 24 selected aptamers showed to contain linear motifs that were grouped into three families and motifs of family I, which contains the sequence GGGGG or similar sequences with a single substitution with either A or U at any position, were detected more frequently. Fourteen ligands were chosen for in silico prediction of secondary structure and revealed presence of loops/hairpins that might be potential regions for interaction with the DENV-1 and -3 RNAs, which may lead to the loss of their original conformation and prevent the viral RNA replication and/or transcriptional process. This is the first description of aptamers against RNA elements of the dengue virus genome that may have important implications in the disease control, since they may be useful for the development of antivirals or of reagents for diagnostic tests.
Biography Adriana Freitas Neves completed his PhD at the age of 30 years from Universidade Federal de Uberlandia, Laboratory of Nanobiotechnology, Minas Gerais, Brazil. She is professor of Universidade Federal de Goiás, Brazil, and coordinates of the Molecular Biology Laboratory, developing work with prostate cancer and infectious diseases. She has published more than 23 papers in reputed journals.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
Page 87 Ajay Ashok et al., Med Chem 2014, 4:12 http://dx.doi.org/10.4172/2161-0444.S1.011
3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA
SurR9C84A exhibits cardioprotective effects against melphalan induced cardiotoxicity in primary human cardiomyocytes Ajay Ashok, Jagat R Kanwar and Rupinder K Kanwar Deakin University School of Medicine, Australia
ancer chemotherapy leads to cardiac toxicity and adverse cardiac muscle injury. Novel therapeutics that salvage cardiac Cdamage (apoptosis) and revive affected cardiomyocytes are urgently required. Survivin, an inhibitor of apoptosis is a bifunctional protein with a role in cell proliferation. We have recently reported the neuroprotective properties of SurR9C84A which is a cell-permeable dominant negative mutant recombinant survivin protein. The cardioprotective nature of SurR9C84A against melphalan induced cardiotoxicity in primary human cardiomyocytes (HCM) was investigated in this study. We hypothesized that SurR9C84A would be a potent cardioprotective agent against melphalan induced cardiotoxicity, by inhibiting cell apoptosis and inducing cell proliferation. The dose of melphalan was optimized to induce cardiotoxicity in HCM and the cardioprotective effects were studied after 4 days of SurR9C84A treatment. Cell proliferation and apoptosis were detected by CyQUANT and Annexin-V kits, respectively. The changes in expression of cardiac damage markers; free cardiac troponin T, creatine kinase and other vital anti-stress proteins were analyzed by immunoblotting. Melphalan treatment induced 40% toxicity in HCM. Cellular uptake of SurR9C84A increased proliferation of HCM, upregulated survivin and proliferating cell nuclear antigen expression, inhibited apoptosis and caused actin regeneration in the damaged HCM. A significant downregulation of f cTnT, creatine kinase, matrix metalloproteinase-9, angiotensin 2 receptor, Bax, interleukin-1β, cytochrome C and caspase-3 was observed. SurR9C84A was nontoxic to normal HCM. In conclusion, our study identifies the cardioprotective nature of bifunctional SurR9C84A in HCM regeneration and its future implications in designing protein therapeutics to relieve the effects of anti-cancer drugs on heart.
Biography Ajay Ashok has completed his Bachelor in Technology (Biotechnology) from SRM University and Masters in Technology from SASTRA University (School of Medical Nanotechnology) with the highest grade awarded for the degree. He is currently pursuing his PhD at Deakin University, School of Medicine, Australia. Due to his merits, he was awarded The Deakin University Post graduate International Research Scholarship for a PhD course in 2012. He had previously presented his other studies at various other reputed conferences such as the World Congress of Cardiology in 2014 and International Nanomedicine Conference, Sydney 2012.
MedChem 2014 MedChem & CADD-2014 Volume 4, Issue 12 ISSN: 2161-0444, Med chem an open access journal December 08-10, 2014
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