DOCSLIB.ORG

Methods for the Investigation of Protein-Ligand Complexes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Methods for the Investigation of Protein-Ligand Complexes Benjamin H Stauch Robinson College University of Cambridge A thesis submitted for the degree of Doctor of Philosophy June 2013 Meinen Eltern. \What we see before us is just one tiny part of the world. We get in the habit of thinking, this is the world, but that's not true at all. The real world is a much darker and deeper place than this, and much of it is occupied by jellyfish and things. We just happen to forget all that. Don't you agree? Two-thirds of earth's surface is ocean, and all we can see with the naked eye is the surface: the skin." Haruki Murakami The Wind-Up Bird Chronicle. \I may not have gone where I intended to go, but I think I have ended up where I needed to be." Douglas Adams The Long Dark Tea-Time of the Soul. Declaration This thesis is the result of my own work and includes nothing which is the outcome of work done in collaboration except where specifically indicated in the text. This thesis does not exceed the specified length limit of 60,000 words as defined by the Biology Degree Committee. This thesis has been typeset in 12pt font using LATEX according to the specifica- tions defined by the Board of Graduate Studies and the Biology Degree Committee. Acknowledgements This Ph.D. has been a long and strange journey. I owe my gratitude to many people I met on the way, and to those who were with me from the start. Although this section is therefore rather long, it is also necessarily incomplete. First and foremost, I would like to thank my supervisor John Over- ington for his leap of faith of accepting me into his group at the EBI, providing me with ideas, inspiration and criticism. Your constant sup- port and advice has made this thesis possible. Daniel Nietlispach is acknowledged for his willingness to provide su- pervision from the side of Cambridge University, and support in and understanding of complicated issues. I owe my deepest gratidude to Helke Hillebrand, Iain Mattaj, and the EMBL International Ph.D. Programme for funding and solving minor and major problems, making me feel like nothing can go wrong. Michele Cianci is thanked for his exceptional commitment, patience and support during most of the experimental work presented in this thesis. Thanks to your hospitality, my numerous trips to Hamburg have never felt like work, even though we have been clocking long hours. I must thank Bernd Simon for his support and expertise during my time in Heidelberg. It was an absolute pleasure working with you, and I like to think that you are the prime example of how EMBL really is held together. The members of my thesis advisory committee, Maja K¨ohnand Ger- ard Kleywegt, are gratefully acknowledged for their duties during my Ph.D., providing constant input and hands-on support. Teresa Carlomagno is acknowledged for accepting me into the EMBL and her supervision during my time at the EMBL Heidelberg. Importantly, my parents and my family, who were essential to me dur- ing my entire education (and before), trusting my judgment and sup- porting me in every which way. This is for you. Sophie Shephard has been a great support through many of the chal- lenges on my way, and I am sure at this stage, together with my parents and John, she will be among the five most relieved people this is coming to a conclusion. Daniel Mende and Christina Mertens have been great friends for many years. It means a lot to me to know I can always rely on you. Felix Kr¨ugerand Nenad Bartoniˇcek have been essential in making me feel at home in Cambridge, and I never had to ask them twice to help me out one of the many times I did. You guys are awesome! Also thanks to you, John and Sophie for proof-reading of this thesis. My housemates Benedetta Baldi and Tamara Steijger are credited for enduring me especially during the last phase of this thesis. Frank Thommen is acknowledged for facilitating many last-minute, non-standard, and semi-official solutions, and work-arounds. Adriana Rullmann has been a most exceptional teacher and inspiration early during my education. Without you I would probably not be here. Thanks for encouraging me to take on slightly thicker `boards'. Julien Orts, Irene Amata, John Kirpatrick, Domenico Sanfelice, Thierry Rohmer, Audron_eLapinait_e,Carmen Fernandez, Teodora Basile, Mag- dalena Rakwalska, and Stephen Fullerton are acknowledged for being great colleagues and friends during my time in Heidelberg. You made it worth it. Patr´ıciaBento, Sam Croset, Gerard van Westen, Louisa Bellis, Shaun McGlinchey, George Papadatos, Rita Santos, and the entire ChEMBL team for their welcoming me and help to settle in to Cambridge and the Genome Campus. It has been a pleasure working with you. Henning Hofmann, J¨orgZielonka, and Carten M¨unkare thanked for giving me confidence and encouraging me to pursue my ambitions, and providing me with a great environment during my master's thesis. I furthermore thank Teresa Tiffert and Robinson College, Cambridge for their support during my graduate studies here. Sander Timmer, Christine Seeliger and Steven Wilder are gratefully ackonwledged for the banter, the long hours on the ergs, the rare hours in the sun, and contributing their part in keeping me going. I must thank Angela^ Gon¸calves and Catalina Schwalie for their will- ingness to casually overlook initial dissents. Tracey Andrew and Milanka Stoijkovic are acknowledged as represen- tatives of the Ph.D. Programme. Their commitment and interest in their `subjects' has been exceptional. I am grateful to Pedro Ballester and Michael Menden for their willing- ness to discuss machine learning related matters. The Cambridge University Cycling Club, and especially Dan Ahearn, Sarah Gallagher, Jenny Haskell, and Ming-Chee Chung, are acknowl- edged for getting me away from the screen and bench, or trying to. Konrad Rudolph is thanked for last-minute support with LATEX type- setting. I want to explicitly thank my friends Karina Mayer, Jonas Brand, Isa Serma, Patrick Schubert, Swetlana Derksen, and Sina Muhler for keeping in touch, visiting, or providing accommodation during my own visits back home. Thomas Weisswange, Martin Weisel, Tim Geppert, Tim Werner, Gosia Drwal, Daniel Gottstein, Felix Reisen, and Frederik Hefke deserve a mention, too. Last but not least, I owe my gratitude to countless people at the EMBL Heidelberg, the EBI, and Cambridge University for making my time in Cambridge and Heidelberg into an experience I will keep dearly. Abstract The interaction of small molecules with biological receptors is fundamental for cellular processes and plays a central role in disease and homeostasis. In this thesis, two multi- disciplinary methods aiding the investigation of protein-ligand interactions are presented that make use of data obtained by diverse experimental techniques, Nuclear Magnetic Resonance (NMR) spectroscopy and X-ray crystallography. In the first part of the thesis, an existing NMR-based method for the determination of ligand binding modes, termed INPHARMA, is improved by incorporating a rigorous model of protein internal motion using the NMR order parameter formalism. In this approach, indirect magnetisation transfer between two competitive ligands relayed by the receptor is simulated computationally and compared to experimental NMR data. This yields a ranking of binding poses, allowing for the true ligand orientations to be selected from a pool of possible complex structures. Using Protein Kinase A (PKA) as a test system, and order parameters extracted from Molecular Dynamics simulations of two PKA-ligand complexes, it is demonstrated that the overestimation of the magnetisation transfer that had been observed when not using a motional model, can be corrected for. Additionally, a `generic' statistical characterisation of protein motional behaviour is obtained by investigating other, unrelated proteins, and applied to increase the ability of the method to discriminate true from decoy ligand orientations in the PKA system. In the second part, the empirical notion that the noble gas xenon tends to bind to ligand binding site of proteins is investigated systematically. It is found that xenon is over-represented in protein ligand binding sites of known structures within the Pro- tein Data Bank, showing dispersive interactions with aliphatic and aromatic protein moieties. A knowledge-based interaction potential for xenon is developed and used to construct a `xenon likeness score' that can discriminate xenon from water molecules and ions. The performance of a classifier based on this score is examined by cross-validation using common performance measures from the field of machine learning, indicating high discrimination power. In a prospective application, xenon binding to the N-terminal domain (NTD) of the molecular chaperone Hsp90 is predicted, and for validation, the X-ray structure of a xenon derivative of Hsp90-NTD is solved, demonstrating that xenon binding sites can be predicted with good accuracy. These findings have implications for fragment-based drug discovery, increasing both the throughput and accuracy of the INPHARMA method that is especially suited for fragment-like, weakly binding ligands, and suggesting the usefulness of adding xenon to standard fragment libraries. Contents Contentsi List of Figuresv List of Tables ix 1 Introduction1 1.1 Fragment based drug design . .2 1.1.1 Fragment library design and fragment elaboration . .4 1.1.2 Biophysical techniques for fragment identification . .7 1.1.2.1 NMR spectroscopy . .9 1.1.2.2 X-ray crystallography . 11 1.1.2.3 Surface plasmon resonance . 13 1.1.2.4 Isothermal titration calorimetry . 13 1.1.2.5 Thermal shift assay . 14 1.1.3 Computational techniques for fragment scanning .
Recommended publications
  • Ion Channels in Drug Discovery

    Ion Channels in Drug Discovery

    Department of Physiology and Pharmacology Karolinska Institutet, Stockholm, Sweden Thesis for doctoral degree (Ph.D.) 2008 Thesis for doctoral degree (Ph.D.) 2008 Ion Channels in Drug Discovery - focus on biological assays Ion Channels in Drug Discovery - focus on biological assays Kim Dekermendjian Ion Channels in Drug Discovery - focus on biological - focus on in Drug assays Channels Discovery Ion Kim Dekermendjian Kim Dekermendjian Stockholm 2008 Department of Physiology and Pharmacology Karolinska Institutet, Stockholm, Sweden Ion Channels in Drug Discovery - focus on biological assays Kim Dekermendjian Stockholm 2008 Main Supervisor: Bertil B Fredholm, Professor Department of Physiology and Pharmacology Karolinska Institutet. Co-Supervisor: Olof Larsson, PhD Associated Director Department of Molecular Pharmacology, Astrazeneca R&D Södertälje. Opponent: Bjarke Ebert, Adjunct Professor Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark. and Department of Electrophysiology, H. Lundbeck A/S, Copenhagen, Denmark. Examination board: Ole Kiehn, Professor Department of Neurovetenskap, Karolinska Institutet. Bryndis Birnir, PhD Docent Department of Clinical Sciences, Lund University. Bo Rydqvist, Professor Department of Physiology and Pharmacology Karolinska Institutet. All previously published papers were reproduced with permission from the publisher. Front page (a) Side view of the GABA-A model; the trans membrane domain (TMD) (bottom) spans through the lipid membrane (32 Å) and partly on the extracellular side (12 Å), while the ligand binding domain (LBD) (top) is completely extracellular (60 Å). (b) The LBD viewed from the extracellular side (diameter of 80 Å). (c) The TMD viewed from the extracellular side. Arrows and ribbons (which correspond to ȕ-strands and Į- helices, respectively) are coloured according to position in each individual subunit sequence, as well as in the TM4 of each subunit which is not bonded to the rest of the model (with permission from Campagna-Slater and Weaver, 2007 Copyright © 2006 Elsevier Inc.).
  • Download (1MB)

    Download (1MB)

    THE IN VITRO METABOLISM OF THREE ANTICANCER DRUGS by Yun Fan B.S., West China University of Medical Sciences, 1996 M.S., West China University of Medical Sciences, 2001 Submitted to the Graduate Faculty of School of Pharmacy in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2007 UNIVERSITY OF PITTSBURGH SCHOOL OF PHARMACY This dissertation was presented by Yun Fan It was defended on March 23, 2007 and approved by Samuel M. Poloyac, Assistant Professor, Pharmaceutical Sciences Raman Venkataramanan, Professor, Pharmaceutical Sciences Jack C. Yalowich, Associate Professor, Pharmacology Michael A. Zemaitis, Professor, Pharmaceutical Sciences Billy W. Day, Professor, Pharmaceutical Sciences ii Copyright © by Yun Fan 2007 iii THE IN VITRO METABOLISM OF THREE ANTICANCER DRUGS Yun Fan, Ph.D. University of Pittsburgh, 2007 Etoposide is a widely used topoisomerase II inhibitor particularly useful in the clinic for treatment of disseminated tumors, including childhood leukemia. However, its use is associated with the increased risk of development of secondary acute myelogenous leukemias. The mechanism behind this is still unclear. It was hypothesized that etoposide ortho-quinone, a reactive metabolite previously shown to be generated in vitro by myeloperoxidase, the major oxidative enzyme in the bone marrow cells from which the secondary leukemias arise, might be a contributor to the development of treatment-related secondary leukemias. Experiments showed that the glutathione adduct of etoposide ortho-quinone was formed in myeloperoxidase- expressing human myeloid leukemia HL60 cells treated with etoposide, that its formation was enhanced by addition of the myeloperoxidase substrate hydrogen peroxide, and that the glutathione adduct level was dependent on myeloperoxidase.
  • Relationship Between the Conformation of the Cyclopeptides Isolated from the Fungus Amanita Phalloides (Vaill. Ex Fr.) Secr. and Its Toxicity

    Relationship Between the Conformation of the Cyclopeptides Isolated from the Fungus Amanita Phalloides (Vaill. Ex Fr.) Secr. and Its Toxicity

    Molecules 2000, 5 489 Relationship Between the Conformation of the Cyclopeptides Isolated from the Fungus Amanita Phalloides (Vaill. Ex Fr.) Secr. and Its Toxicity M.E. Battista, A.A. Vitale and A.B. Pomilio PROPLAME-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Natu- rales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, 1428 Buenos Aires, Argentina E-mail: [email protected] Abstract: The electronic structures and conformational studies of the cyclopeptides, O- methyl-α-amanitin, phalloidin and antamanide, were obtained from molecular parameters on the basis of semiempiric and ab initio methods. Introduction During this century Amanita phalloides - the most toxic fungus known up to now - has been studied from different points of view. This basidiomycete biosynthesizes mono- and bicyclic peptides com- posed of rare amino acids. In order to determine the structure/activity relationships chemical modifica- tions were carried out and the properties of these compounds were evaluated. These results were con- firmed by studying the conformations of three selected compounds representative of the major groups of the macroconstituents of this fungus. Experimental Hyperchem package (HyperCube, version 5.2) was used for semiempirical studies, the molecular geometry being optimized by STO-631G. Net charges were calculated with HyperCube PM3 and the Polack-Ribiere algoritm. GAUSSIAN 98 was used for ab initio studies. Results and Discussion We were interested in obtaining information on the conformations that the cyclic peptides may adopt and about the potential energy maps in order to locate the regions related to the binding to pro- tein molecules, such as F-actin and RNA-polymerase.
  • Nicole Goodwin Macmillan Group Meeting April 21, 2004

    Nicole Goodwin Macmillan Group Meeting April 21, 2004

    Discodermolide A Synthetic Challenge Me Me Me HO Me O O OH O NH2 Me Me OH O Me Me OH Nicole Goodwin MacMillan Group Meeting April 21, 2004 Me Me Me HO Discodermolide Me O O OH O NH2 Isolation and Biological Activity Me Me OH O Me Me OH ! Isolated in 1990 by the Harbor Branch Oceanographic Institution from the Caribbean deep-sea sponge Discodermia dissoluta ! Not practical to produce discodermolide from biological sources ! 0.002% (by mass) isolation from frozen sponge ! must be deep-sea harvested at a depth in excess of 33 m ! Causes cell-cycle arrest at the G2/M phase boundary and cell death by apoptosis ! Member of an elite group of natural products that act as microtubule-stabilizing agent and mitotic spindle poisons ! Taxol, epothilones A and B, sarcodictyin A, eleutherobin, laulimalide, FR182877, peloruside A, dictyostatin ! Effective in Taxol-resistant carcinoma cells ! presence of a small concentration of Taxol amplified discodermolide's toxicity by 20-fold ! potential synergies with the combination of discodermolide with Taxol and other anticancer drugs ! Licensed by Novartis from HBOI in 1998 as a new-generation anticancer drug 1 Cell Apoptosis M - Mitosis G0 Discodermolide disrupts the G2/M phases of the cell cycle. Resting Discodermolide, like Taxol, inhibits microtubule depolymerization by binding G1 - Gap 1 to tubulin. G2 - Gap 2 cells increase in size, cell growth control checkpoint no microtubules = no spindle fiber new proteins formation S - Synthesis DNA replication Me Me Me HO Discodermolide Me O O OH O NH2 Isolation
  • United States Patent (19) 11 Patent Number: 5,789,605 Smith, I Et Al

    United States Patent (19) 11 Patent Number: 5,789,605 Smith, I Et Al

    IIIUSOO5789605A United States Patent (19) 11 Patent Number: 5,789,605 Smith, I et al. 45) Date of Patent: Aug. 4, 1998 54 SYNTHETICTECHNIQUES AND Jacquesy et al., "Metabromation Du Dimethyl-2, 6 Phenol INTERMEDIATES FOR POLYHYDROXY, Et De Son Ether Methylique En Milieu Superacide", Tetra DENYL LACTONES AND MIMCS hedron, 1981, 37, 747-751. THEREOF Kim et al., "Conversion of Acetals into Monothioacetals, O-Alkoxyazides and O-Alkoxyalkyl Thioacetates with 75) Inventors: Amos B. Smith, III. Merion; Yuping Magnesium Bromide". Tetra, lett, 1989, 30(48), Qiu; Michael Kaufman, both of 6697-6700. Philadelphia; Hirokaza Arimoto, Longley et al., "Discodermolide-A New, Marine-Derived Drexel Hill, all of Pa.; David R. Jones, Immunosuppressive Compound". Transplantation, 1991. Milford, Ohio; Kaoru Kobayashi, 52(4) 650-656. Osaka, Japan Longley et al., "Discodermolide-A New, Marine-Derived Immunosuppressive Compound". Transplantation, 1991. 73 Assignee: Trustees of the University of 52(4), 657-661. Pennsylvania, Philadelphia, Pa. Longley et al., "Immunosuppression by Discodermolide". Ann. N.Y. Acad. Sci., 1993. 696, 94-107. (21) Appl. No.:759,817 Nerenburg et al., "Total Synthesis of the Immunosuppres 22 Filed: Dec. 3, 1996 sive Agent (-)-Discodermolide". J. Am. Chem, Soc., 1993, 115, 12621-12622. (51) Int. Cl. ................. C07D407/06; C07D 319/06; Paterson, I. et al., "Studies Towards the Total Synthesis of CO7D 309/10 the Marine-derived Immunosuppressant Discodermolide; (52) U.S. Cl. .......................... 549/370; 549/374; 549/417 Asymmetric Synthesis of a C-Cö-Lactone Subunit". J. (58) Field of Search ..................................... 549/370,374, Chen. Soc. Chen, Commun., 1993, 1790-1792. 549/417 Paterson, I. et al., "Studies Towards the Total Synthesis of the Marine-derived Immunosuppresant Discodermolide; 56 References Cited Asymmetric Synthesis of a C-C Subunit".
  • Dissertation.Pdf (1.198Mb)

    Dissertation.Pdf (1.198Mb)

    Syntheses and Bioactivities of Targeted and Conformationally Restrained Paclitaxel and Discodermolide Analogs Chao Yang Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University In the partial fulfillment of the requirement for the degree of Doctor of Philosophy In Chemistry Dr. David G. I. Kingston, Chairman Dr. Karen Brewer Dr. Paul R. Carlier Dr. Felicia. Etzkorn Dr. Harry W. Gibson August 26 2008 Blacksburg, Virginia Keywords: Taxol, drug targeting, , thio-taxol, tubulin-binding conformation, , T-taxol conformation, macrocyclic taxoids, discodermolide Copyright 2008, Chao Yang Syntheses and Bioactivities of Targeted and Conformationally Restrained Paclitaxel and Discodermolide Analogs Chao Yang Abstract Paclitaxel was isolated from the bark of Taxus brevifolia in the late 1960s. It exerts its biological effect by promoting tubulin polymerization and stabilizing the resulting microtubules. Paclitaxel has become one of the most important current drugs for the treatment of breast and ovarian cancers. Studies aimed at understanding the biologically active conformation of paclitaxel bound on β–tubulin are described. In this work, the synthesis of isotopically labeled taxol analogs is described and the REDOR studies of this compound complexed to tubulin agrees with the hypothesis that palictaxel adopts T-taxol conformation. Based on T-taxol conformation, macrocyclic analogs of taxol have been prepared and their biological activities were evaluated. The results show a direct evidence to support T-taxol conformation. (+) Discodermolide is a polyketide isolated from the Caribbean deep sea sponge Discodermia dissoluta in 1990. Similar to paclitaxel, discodermolide interacts with tubulin and stabilizes the microtubule in vivo. Studies aimed at understanding the biologically active conformation of discodermolide bound on β–tubulin are described.
  • Exploring Non-Covalent Interactions Between Drug-Like Molecules and the Protein Acetylcholinesterase

    Exploring Non-Covalent Interactions Between Drug-Like Molecules and the Protein Acetylcholinesterase

    Exploring non-covalent interactions between drug-like molecules and the protein acetylcholinesterase Lotta Berg Doctoral Thesis, 2017 Department of Chemistry Umeå University, Sweden This work is protected by the Swedish Copyright Legislation (Act 1960:729) ISBN: 978-91-7601-644-2 Elektronisk version tillgänglig på http://umu.diva-portal.org/ Printed by: VMC-KBC Umeå Umeå, Sweden, 2017 “Life is a relationship between molecules, not a property of any one molecule” Emile Zuckerkandl and Linus Pauling 1962 i Table of contents Abstract vi Sammanfattning vii Papers covered in the thesis viii List of abbreviations x 1. Introduction 1 1.1. Drug discovery 1 1.2. The importance of non-covalent interactions 1 1.3. Fundamental forces of non-covalent interactions 2 1.4. Classes of non-covalent interactions 3 1.5. Hydrogen bonds 3 1.5.1. Definition of the hydrogen bond 3 1.5.2. Classical and non-classical hydrogen bonds 4 1.5.3. CH∙∙∙Y hydrogen bonds 5 1.6. Interactions between aromatic rings 6 1.7. Thermodynamics of binding 7 1.8. The essential enzyme acetylcholinesterase 8 1.8.1. The relevance of research focused on AChE 8 1.8.2. The structure of AChE 9 1.8.3. AChE in drug discovery 10 2. Scope of the thesis 12 3. Background to techniques and methods 13 3.1. Structure determination by X-ray crystallography 13 3.1.1. The significance of crystal structures of proteins 13 3.1.2. Data collection and structure refinement 13 3.1.3. Electron density maps 14 3.1.4.
  • Total Synthesis of the Marine Natural Product (+)-Discodermolide in Multigram Quantities*

    Total Synthesis of the Marine Natural Product (+)-Discodermolide in Multigram Quantities*

    Pure Appl. Chem., Vol. 79, No. 4, pp. 685–700, 2007. doi:10.1351/pac200779040685 © 2007 IUPAC Total synthesis of the marine natural product (+)-discodermolide in multigram quantities* Stuart J. Mickel Novartis Pharma AG, CHAD, WKL-684.2.31 Klybeckstrasse, 4052 Basel, Switzerland Abstract: The novel polyketide (+)-discodermolide was isolated in very small quantities from sponge extracts. This compound is one of several microtubule stabilizers showing promise as novel chemotherapeutic agents for the treatment of cancer. The clinical evaluation of this and similar compounds is hampered by lack of material, and at present, the only way to obtain the necessary quantities is total chemical synthesis. Keywords: discodermolide; boron aldol reaction; isolation; side products; olefination. INTRODUCTION The marine natural product (+)-discodermolide 1 was isolated by workers at the Harbor Branch Oceanographic Institute from the deep-sea sponge Discodermia dissoluta in 1990 [1]. It is obtained from the sponge in extremely small quantities, 0.002 % in the frozen material. This compound is one of several natural products exhibiting inhibition of microtubule depolymerization and as such shows considerable promise as a novel chemotherapeutic agent for the treatment of cancer [2]. In contrast to Taxol®, another microtubule stabilizer, (+)-1 shows activity in the Taxol-resistant cell lines which over- express P-glycoprotein, the multidrug-resistant transporter. The similarities and differences between (+)-1 and Taxol have recently been discussed in detail [3]. The structure of (+)-1 consists of a linear polypropionate chain interrupted by 3 cis-olefins. It con- tains 13 chiral centers, 6 of which are hydroxyl groups, one esterified as a lactone, another as a car- bamic acid ester.
  • Marine Natural Products: a Source of Novel Anticancer Drugs

    Marine Natural Products: a Source of Novel Anticancer Drugs

    marine drugs Review Marine Natural Products: A Source of Novel Anticancer Drugs Shaden A. M. Khalifa 1,2, Nizar Elias 3, Mohamed A. Farag 4,5, Lei Chen 6, Aamer Saeed 7 , Mohamed-Elamir F. Hegazy 8,9, Moustafa S. Moustafa 10, Aida Abd El-Wahed 10, Saleh M. Al-Mousawi 10, Syed G. Musharraf 11, Fang-Rong Chang 12 , Arihiro Iwasaki 13 , Kiyotake Suenaga 13 , Muaaz Alajlani 14,15, Ulf Göransson 15 and Hesham R. El-Seedi 15,16,17,18,* 1 Clinical Research Centre, Karolinska University Hospital, Novum, 14157 Huddinge, Stockholm, Sweden 2 Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE 106 91 Stockholm, Sweden 3 Department of Laboratory Medicine, Faculty of Medicine, University of Kalamoon, P.O. Box 222 Dayr Atiyah, Syria 4 Pharmacognosy Department, College of Pharmacy, Cairo University, Kasr el Aini St., P.B. 11562 Cairo, Egypt 5 Department of Chemistry, School of Sciences & Engineering, The American University in Cairo, 11835 New Cairo, Egypt 6 College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China 7 Department of Chemitry, Quaid-i-Azam University, Islamabad 45320, Pakistan 8 Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, Germany 9 Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Dokki, 12622 Giza, Egypt 10 Department of Chemistry, Faculty of Science, University of Kuwait, 13060 Safat, Kuwait 11 H.E.J. Research Institute of Chemistry,
  • Clinical Pharmacology of Antiмcancer Agents

    Clinical Pharmacology of Antiмcancer Agents

    A CLINI CLINICAL PHARMACOLOGY OF NTI- C ANTI-CANCER AGENTS C AL PHARMA AN Cristiana Sessa, Luca Gianni, Marina Garassino, Henk van Halteren www.esmo.org C ER A This is a user-friendly handbook, designed for young GENTS medical oncologists, where they can access the essential C information they need for providing the treatment which could OLOGY OF have the highest chance of being effective and tolerable. By finding out more about pharmacology from this handbook, young medical oncologists will be better able to assess the different options available and become more knowledgeable in the evaluation of new treatments. ESMO ESMO Handbook Series European Society for Medical Oncology CLINICAL PHARMACOLOGY OF Via Luigi Taddei 4, 6962 Viganello-Lugano, Switzerland Handbook Series ANTI-CANCER AGENTS Cristiana Sessa, Luca Gianni, Marina Garassino, Henk van Halteren ESMO Press · ISBN 978-88-906359-1-5 ISBN 978-88-906359-1-5 www.esmo.org 9 788890 635915 ESMO Handbook Series handbook_print_NEW.indd 1 30/08/12 16:32 ESMO HANDBOOK OF CLINICAL PHARMACOLOGY OF ANTI-CANCER AGENTS CM15 ESMO Handbook 2012 V14.indd1 1 2/9/12 17:17:35 ESMO HANDBOOK OF CLINICAL PHARMACOLOGY OF ANTI-CANCER AGENTS Edited by Cristiana Sessa Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Luca Gianni Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Marina Garassino Oncology Department, Istituto Nazionale dei Tumori, Milan, Italy Henk van Halteren Department of Internal Medicine, Gelderse Vallei Hospital, Ede, The Netherlands ESMO Press CM15 ESMO Handbook 2012 V14.indd3 3 2/9/12 17:17:35 First published in 2012 by ESMO Press © 2012 European Society for Medical Oncology All rights reserved.
  • Biological Target and Its Mechanism He Zuan* Department of Pharmacology, School of Medicine,Shenzhen University, Shenzhen 518000, China

    Biological Target and Its Mechanism He Zuan* Department of Pharmacology, School of Medicine,Shenzhen University, Shenzhen 518000, China

    OPEN ACCESS Freely available online Journal of Cell Signaling Editorial Biological Target and Its Mechanism He Zuan* Department of Pharmacology, School of Medicine,Shenzhen University, Shenzhen 518000, China EDITORIAL NOTE 1. There is no direct change in the biological target, but the binding of the substance stops other endogenous substances (such Biological target is whatsoever within an alive organism to which as triggering hormones) from binding to the target. Contingent some other entity (like an endogenous drug or ligand) is absorbed on the nature of the target, this effect is mentioned as receptor and binds, subsequent in a modification in its function or antagonism, ion channel blockade or enzyme inhibition. behaviour. For examples of mutual biological targets are nucleic acids and proteins. Definition is context dependent, and can refer 2. A conformational change in the target is induced by the stimulus to the biological target of a pharmacologically active drug multiple, which results in a change in target function. This change in function the receptor target of a hormone like insulin, or some other target can mimic the effect of the endogenous substance in which case of an external stimulus. Biological targets are most commonly the effect is referred to as receptor agonism or be the opposite of proteins such as ion channels, enzymes, and receptors. The term the endogenous substance which in the case of receptors is referred "biological target" is regularly used in research of pharmaceutical to as inverse agonism. to describe the nastive protein in body whose activity is altered Conservation Ecology: These biological targets are conserved by a drug subsequent in a specific effect, which may a desirable across species, making pharmaceutical pollution of the therapeutic effect or an unwanted adverse effect.
  • Uncovering New Drug Properties in Target-Based Drug-Drug Similarity Networks

    Uncovering New Drug Properties in Target-Based Drug-Drug Similarity Networks

    bioRxiv preprint doi: https://doi.org/10.1101/2020.03.12.988600; this version posted March 12, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Uncovering new drug properties in target-based drug-drug similarity networks Lucret¸ia Udrescu1, Paul Bogdan2, Aim´eeChi¸s3, Ioan Ovidiu S^ırbu3,6, Alexandru Top^ırceanu4, Renata-Maria V˘arut¸5, Mihai Udrescu4,6* 1 Department of Drug Analysis, "Victor Babe¸s",University of Medicine and Pharmacy Timi¸soara,Timi¸soara,Romania 2 Ming Hsieh Department of Electrical Engineering, University of Southern California, Los Angeles, CA, USA 3 Department of Biochemistry, "Victor Babe¸s"University of Medicine and Pharmacy Timi¸soara,Timi¸soara,Romania 4 Department of Computer and Information Technology, Politehnica University of Timi¸soara,Timi¸soara,Romania 5 Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, Romania 6 Timi¸soaraInstitute of Complex Systems, Timi¸soara,Romania * [email protected] Abstract Despite recent advances in bioinformatics, systems biology, and machine learning, the accurate prediction of drug properties remains an open problem. Indeed, because the biological environment is a complex system, the traditional approach { based on knowledge about the chemical structures { cannot fully explain the nature of interactions between drugs and biological targets. Consequently, in this paper, we propose an unsupervised machine learning approach that uses the information we know about drug-target interactions to infer drug properties.