Drug discovery strategies and methods 2004 makriyannis biegel

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DRUG DISCOVERY STRATEGIES METHODS EDITED BY ALEXANDROSMAKRIYANNIS DIANEB~EGEL Center for Drug Discovery University of Connecticut Storrs, Connecticut, U.S.A Copyright 2004 by Marcel Dekker, Inc All Rights Reserved Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book The material contained herein is not intended to provide specific advice or recommendations for any specific situation Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 0-8247-0691-9 This book is printed on acid-free paper Headquarters Marcel Dekker, Inc 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities For more information, write to Special Sales/Professional Marketing at the headquarters address above Copyright n n 2004 by Marcel Dekker, Inc All Rights Reserved Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher Current printing (last digit): 10 PRINTED IN THE UNITED STATES OF AMERICA Copyright 2004 by Marcel Dekker, Inc All Rights Reserved Preface Drug research encompasses diverse branches of science united by a common goal, namely, developing novel therapeutic agents and understanding their molecular mechanisms of action This process is a lengthy, exacting, and expensive undertaking that involves integration of data from different fields and culminates in the final product—a new drug in the marketplace In the past decade, progress in drug research has flourished because of major contributions from a variety of disciplines The material presented in this volume focuses on a number of research topics that have provided critical information in the field of drug discovery Several chapters present techniques that extend our understanding of the three-dimensional structure of macromolecules, principally proteins, but also nucleic acid polymers and organized lipid and carbohydrate assemblies As greater structural data on the these molecules become available, information can be obtained on their interactions with small endogenous ligand drug molecules as well as on the interactions between two or more of these biopolymers Such knowledge enhances our overall understanding of the biochemical systems of interest and their relevance for therapeutic discovery In addition to the basic knowledge gained by such research, the data provide a solid basis for the development of novel drugs with greater potencies, higher specificities of action, and reduced side effects Another area of research covered in this book is the in vivo anatomical localization of potential therapeutics using PET and SPECT analysis (Chapter 5) These techniques allow researchers to pinpoint the localization of high-affinity ligands in the living organism with high accuracy, thus giving researchers a window on the functions of the brain and other organs and on the sites of action of potential therapeutic agents Such studies will provide a blueprint for the design of pharmacological Copyright 2004 by Marcel Dekker, Inc All Rights Reserved agents that will target specific regions of affected organs and deliver therapeutic actions rapidly and with high specificity High throughput methods have increased our capacity for appropriate candidate compounds selection and also for developing libraries of novel compounds from which such candidates can be selected Chapter discusses the use of solid-phase synthesis for the high throughput production of peptides and other small molecules In addition, as discussed in Chapter on peptidomimetics, the swift production of novel leads holds considerable promise for future discovery of novel therapeutic agents The investigation of therapeutic targets for cannabinoid sites of action has already generated considerable interest within the field of drug discovery, and Chapter 4, which details the results of such studies, highlights the importance of target-based studies The enhanced appreciation of the role of stereochemistry in drug action has focused efforts on understanding the conformation of drugs as they bind to their target receptor Studies of the diverse effects of cannabinoids and the development of compounds that employ the information gleaned from the ligand/receptor data should provide substantial insight into their molecular mechanisms of action Future research will promote the development of drugs that are capable of higher specificity longer half-lives, and lessened toxicity In studies of potential antiviral therapies, the understanding of viral target molecules is essential for the production of effective medications that interact specifically in the viral life cycle and gene products, which will result in lowering drug toxicity to the host and enhancing the antiviral activity of the pharmacotherapy As the nature of viral infectivity, cell growth, death, and receptor biology are elucidated, the methods and paradigms for development of highly specific medications will provide superior treatments for a number of diseases that pose a terrible burden worldwide (Chapters 10 and 11) From the fields of proteomics and genomics that hold significant promise for unique medications, several areas of biology have also found applications in the drug discovery arena The study of regulatory molecules and oncogenes has opened new avenues in drug therapy, as discussed in Chapter on G-protein-coupled receptors and Chapter on SRC homology domains Research on protein misfolding (Chapter 9), which has been implicated in neurodegenerative diseases, has highlighted the need to enhance our understanding of structural alterations in normal proteins products Chapter details the development of such research, and asserts that only as we understand the basic physical mechanisms of such alterations can new therapeutic regimens be proposed and tested Copyright 2004 by Marcel Dekker, Inc All Rights Reserved The topics included in this volume are not intended to be allinclusive Our approach has been eclectic, in an effort to bring the reader the most exciting aspects of drug discovery, along with the methods that show the most promise in enhancing the discovery process The chapters presented in this book have been contributed by specialists in their areas of research and will provide a contemporary picture of the overall field of drug discovery to scientists from diverse disciplines Alexandros Makriyannis Diane Biegel Copyright 2004 by Marcel Dekker, Inc All Rights Reserved Contents Preface Contributors Protein Crystallography in Structure-Based Drug Design Xiayang Qiu and Sherin S Abdel-Meguid Src Homology-2 Domains and Structure-Based, SmallMolecule Library Approaches to Drug Discovery Chester A Metcalf III and Tomi Sawyer Three-Dimensional Structure of the Inhibited Catalytic Domain of Human Stromelysin-1 by Heteronuclear NMR Spectroscopy Paul R Gooley Cannabinergics: Old and New Possibilities Andreas Goutopoulos and Alexandros Makriyannis Development of PET and SPECT Radioligands for Cannabinoid Receptors S John Gatley, Andrew N Gifford, Yu-Shin Ding, Ruoxi Lan, Qian Liu, Nora D Volkow, and Alexandros Makriyannis Copyright 2004 by Marcel Dekker, Inc All Rights Reserved Structural and Pharmacological Aspects of Peptidomimetics Peter W Schiller, Grazyna Weltrowska, Ralf Schmidt, Thi M.-D Nguyen, Irena Berezowska, Carole Lemieux, Ngoc Nga Chung, Katharine A Carpenter, and Brian C Wilkes Linkers and Resins for Solid-Phase Synthesis: 1997-1999 Pan Li, Elaine K Kolaczkowski, and Steven A Kates Allosteric Modulation of G-Protein-Coupled Receptors: Implications for Drug Action Angeliki P Kourounakis, Pieter van der Klein, and Ad P I IJzerman Protein Misfolding and Neurodegenerative Disease: Therapeutic Opportunities Harry LeVine III 10 Uncoating and Adsorption Inhibitors of Rhinovirus Replication Guy D Diana and Adi Treasurywala 11 Profiles of Prototype Antiviral Agents Interfering with the Initial Stages of HIV Infection E De Clercq Copyright 2004 by Marcel Dekker, Inc All Rights Reserved Contributors Sherin S Abdel-Meguid Suntory Pharmaceutical Research Laboratories, Cambridge, Massachussets, U.S.A Irena Berezowska Quebec, Canada Clinical Research Institute of Montreal, Montreal, Katharine A Carpenter treal, Quebec, Canada Ngoc Nga Chung Quebec, Canada Clinical Research Institute of Montreal, Mon- Clinical Research Institute of Montreal, Montreal, Eric De Clercq Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium Guy D Diana ViroPharma, Inc Exton, Pennsylvania, U.S.A Yu-Shin Ding U.S.A Brookhaven National Laboratory, Upton, New York, S John Gatley U.S.A Brookhaven National Laboratory, Upton, New York, Andrew N Gifford York, U.S.A Paul R Gooley Brookhaven National Laboratory, Upton, New University of Melbourne, Parkville, Victoria, Australia Copyright 2004 by Marcel Dekker, Inc All Rights Reserved Andreas Goutopoulos Serono Reproductive Biology Institute, Rockland, Massachusetts, U.S.A Ad P IJzerman Leiden University, Leiden, The Netherlands Steven A Kates Surface Logix, Inc., Brighton, Massachusetts, U.S.A Elaine K Kolaczkowski chussetts, U.S.A Vertex Pharmaceuticals, Cambridge, Massa- Angeliki P Kouranakis Greece University of Thessaloniki, Thessaloniki, Ruoxi Lan University of Connecticut, Storrs, Connecticut, U.S.A Carole Lemieux Quebec, Canada Clinical Research Institute of Montreal, Montreal, Harry LeVine III University of Kentucky, Lexington, Kentucky, U.S.A Pan Li Vertex Pharmaceuticals, Cambridge, Massachusettes, U.S.A Qian Liu University of Connecticut, Storrs, Connecticut, U.S.A Alexandros Makriyannis U.S.A Chester A Metcalf III sachusetts, U.S.A Thi M.-D Nguyen Quebec, Canada University of Connecticut, Storrs, Connecticut, ARIAD Pharmaceuticals, Inc., Cambridge, Mas- Clinical Research Institute of Montreal, Montreal, Xiayang Qiu SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A Tomi Sawyer setts, U.S.A ARIAD Pharmaceuticals, Inc., Cambridge, Massachu- Copyright 2004 by Marcel Dekker, Inc All Rights Reserved Clinical Research Institute of Montreal, Montreal, Peter W Schiller Quebec, Canada Ralf Schmidt Canada Clinical Research Institute of Montreal, Montreal, Quebec, Pfizer Central Research, Groton, Connecticut, U.S.A Adi Treasurywala Pieter van der Klein Nora D Volkow NIDA, Bethesda, Maryland, U.S.A Grazyna Weltrowska Quebec, Canada Brian C Wilkes Quebec, Canada Leiden University, Leiden, The Netherlands Clinical Research Institute of Montreal, Montreal, Clinical Research Institute of Montreal, Montreal, Copyright 2004 by Marcel Dekker, Inc All Rights Reserved Figure Tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H )-one (TIBO) derivatives (A) R82913 and (B) R86183 (with a chlorine substituted in the 9- or 8position, respectively) Figure (A) 1-(2-Hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) (B) 5Isopropyl-1-(ethoxymethyl)-6-benzyluracil (I-EBU, MKC-442) Copyright 2004 by Marcel Dekker, Inc All Rights Reserved described as HIV-1-specific RT inhibitors (for a review on the HIV-1specific RT inhibitors, see Refs 28 and 64) The HEPT and TIBO derivatives were discovered as the result of a systematic evaluation for anti-HIV activity in cell culture They were later found to achieve their anti-HIV-1 activity through an interaction with the HIV-1 RT In contrast, nevirapine, pyridinone, and BHAP emerged from a screening program for HIV-1 RT inhibitors The anti-HIV-1 activity of these compounds was subsequently confirmed in cell culture Like the HEPT and TIBO derivatives, the 2V,5V-bis-O-(tert-butyldimethylsilyl)-3Vspiro-5VV-(4VV-amino-1VV,2VV-oxathiole-2VV,2VV-dioxide)-pyrimidine (TSAO) derivatives (Fig 9) [65,66] and a-anilinophenylacetamides (a-APA) (Fig 10) [67] were discovered through the evaluation of their anti-HIV activity in cell culture Subsequently, they were found to act as specific inhibitors of HIV-1 RT Yet other compounds have been found to inhibit HIV-1 replication through a specific interaction with HIV-1 RT (i.e., quinoxaline S-2720 [68], 5-chloro-3-(phenylsulfonyl)indole-2-carboxamide [69], dihydrothiazoloisoindolones [70] and a number of natural substances (e.g., calanolide A and inophyllums, from the tropical rain forest trees Calophyllum lanigerum and Calophyllum inophyllum, respectively) [71,72] All these and yet other compounds could be considered to be NNRTIs The most potent among the NNRTIs, some of the HEPT derivatives (E-EBU-dM) [63] and a- Figure 2V,5V-Bis-O-(tert-butyldimethylsilyl)-3V-spiro-5W-(4W-amino-1W,2W-oxathiole-2W,2W-dioxide)pyrimidine (TSAO) derivatives TSAO-T, TSAO-m3T, and TSAO-e3T Copyright 2004 by Marcel Dekker, Inc All Rights Reserved Figure 10 a-Anilinophenylacetamide (a-APA) derivatives (A) R18893, (B) R88703, and (C) R89439 APA derivatives (R89439) [67], inhibit HIV-1 replication at a concentration of approximately ng/mL, that is, 100,000-fold below the cytotoxicity threshold While the ddNs and ANPs must be converted intracellularly to their 5V-triphosphates (ddNTPs) or diphosphate derivatives before they can interact as competitive inhibitors/alternate substrates with regard to the natural substrates (dNTPs), the NNRTIs not need any metabolic conversion to interact, noncompetitively with respect to the dNTPs, at an allosteric, non –substrate binding site of the HIV-1 RT Through the analysis of NNRTI-resistant mutants, combined with site-directed mutagenesis studies, it has become increasingly clear which amino acid residues are involved in the interaction of the NNRTIs with HIV-1 RT, and, since the conformation of the HIV-1 RT has been resolved at 3.0 A˚ resolution [73], it is now possible to visualize the binding site of the NNRTIs [74] The antiviral activity spectrum of the NNRTIs is limited to HIV-1, probably because only HIV-1 RT contains a pocket site at which the Copyright 2004 by Marcel Dekker, Inc All Rights Reserved NNRTIs may bind The high specificity displayed by the NNRTIs in their binding to HIV-1 RT signals that it should, a priori, be relatively easy for the enzyme (and the virus) to escape the inhibitory effects of the NNRTIs through mutations of the amino acid residues that either are directly involved in the binding of the NNRTIs or contribute to the configuration of the pocket that is ideal for NNRTI binding From pilot studies carried out in the clinic with the NNRTIs TIBO R82913 [75] and pyridinone L-697,661 [76], it appears that the compounds are well tolerated and not cause toxic side effects Most of the HIV-1 isolates obtained from the patients treated with TIBO R82913 appeared to be as sensitive to the compound as wild-type virus; only two HIV-1 variants were isolated, showing a sensitivity that was reduced 20-fold or more than 100-fold, the latter being caused by a mutation (Tyr ! Leu) at position 188 of the RT [77] In fact, the latter mutation was lost upon passaging the virus in vitro in cord blood lymphocytes Following treatment of the patients with pyridinone L-697,661, drug-resistant HIV-1 variants appeared that contained mutations at the RT positions 103 (Lys ! Asn) and 181 (Tyr ! Cys) [76] HIV-1 resistance to NNRTIs rapidly arises following passage of the virus in cell culture in the presence of the compounds The 181 Tyr ! Cys mutation is most commonly seen, and it leads to resistance, or at least to reduced sensitivity, to most of the NNRTIs (i.e., TIBO, HEPT, nevirapine, pyridinone, BHAP, TSAO, a-APA) [78 – 84] The 188 Tyr ! His mutation is associated with resistance to TIBO [85], but not nevirapine [82] The 103 Lys ! Asn mutation is associated mainly with resistance to TIBO and pyridinone [78,85] The 100 Leu ! Ile mutation is associated mainly with resistance to TIBO [85,86] The 106 Val ! Ala mutation mainly leads to resistance to nevirapine and HEPT [83,84,87] The 138 Glu ! Lys mutation is responsible for resistance to TSAO [88,89] The 190 Gly ! Glu mutation accounts for resistance to quinoxaline [68], while also leading to a dramatic reduction in RT activity [90]; and the 236 Pro ! Leu mutation is responsible for resistance to BHAP [91] The rapid emergence of drug-resistant HIV-1 mutants under selective pressure of the HIV-1-specific RT inhibitors has been generally viewed as a limitation for, if not an argument against, the clinical usefulness of these compounds Yet, several aspects of virus – drug resistance, particularly with respect to the NNRTIs, remain to be addressed before the problem of resistance can be fully assessed For example, how pathogenic are drugresistant variants in comparison to wild-type virus? How readily are such drug-resistant variants transmitted from one person to another? Do virus- Copyright 2004 by Marcel Dekker, Inc All Rights Reserved resistant variants persist when the drug is withdrawn, or they readily revert to the wild type? Assuming that the development of drug resistance may indeed compromise the clinical usefulness of the NNRTIs, how might this problem be prevented or circumvented? If resistance develops to one of the NNRTIs, treatment could be switched to any of the other NNRTIs to which the virus has retained sensitivity For example, 5-chloro-3-(phenylsulfonyl)indole-2-carboxamide [69] is active against the HIV-1 strains that, because of the 103 Lys ! Asn mutation or 181 Tyr ! Cys mutation, have acquired resistance to various other NNRTIs (i.e., TIBO, nevirapine, pyridinone, BHAP) The a-APA derivative R89439 [67] is active against the 100 Leu ! Ile mutant, which is resistant to the TIBO derivatives R82913 and R86183 Within the TIBO class, a minor chemical modification, the shifting of the chlorine atom from the 9-position (R82913) to the 8-position (R86183), suffices to restore activity against the 181 Tyr ! Cys mutant [92] Similarly, pyridinone L-702,019, which differs from its predecessor L-696,229 only by the addition of two chlorine atoms (in the benzene ring) and substitution of sulfur for oxygen (in the pyridine ring), remains remarkably active against HIV-1 mutants containing the 103 Lys ! Asn or 181 Tyr ! Cys mutation [93] In some instances resistance to one of the NNRTIs may even be accompanied by hypersensitivity to others: the 236 Pro ! Leu mutation, which causes resistance to BHAP, confers 10-fold increased sensitivity to TIBO, nevirapine, and pyridinone [91] The 181 Tyr ! Cys mutation, which is responsible for resistance to most NNRTIs, has been found to suppress the 215 mutation (Thr ! Phe/ Tyr), which is responsible for resistance to AZT [94], and, vice versa, the 181 Tyr ! Cys mutation can be suppressed by AZT, which thus means that the mutations at positions 181 and 215 counteract each other Yet other mutations have proved to counteract each other: 236 Pro ! Leu vs 138 Glu ! Lys, and, as mentioned, 215 Thr ! Phe/Tyr vs 184 Met ! Val, and 215 Thr ! Phe/Tyr vs 74 Leu ! Val [47] Based on the resistance mutations that counteract each other, combinations of different drugs could be envisaged—namely, combinations of AZT with either TIBO, a-APA, HEPT, nevirapine, or pyridinone—and these two drug combinations could be extended to three- or four-drug combinations by the addition of another ddN analogue (such as 3TC) and/or another NNRTI (such as BHAP or TSAO) What would seem to be an attractive approach to the prevention of resistance development is the ‘‘knocking-out’’ strategy [95] If NNRTIs, Copyright 2004 by Marcel Dekker, Inc All Rights Reserved such as BHAP (U-88204 or U-90152), are used from the start at a sufficiently high concentration (i.e., or AM, respectively), they completely suppress virus replication [96,97], with the result that the virus is ‘‘knocked out’’ and does not have the opportunity to become resistant If U-90152 is combined with AZT, the concentrations of the individual drugs can be lowered to achieve total virus clearance [97] Five NNRTIs (TIBO, HEPT, nevirapine, pyridinone, and BHAP) have been shown to ‘‘knock out’’ HIV-1 in cell culture when used at concentrations (1 –10 Ag/mL) that are nontoxic to the cells [95] That the virus was really knocked out, and thus the cell culture cleared (‘‘sterilized’’) from the HIV-1 infection by the NNRTIs, was ascertained by two successive rounds of 35-cycle PCR (polymerase chain reaction) analysis, which failed to reveal the presence of any proviral DNA [95] Thus, when used at ‘‘knocking-out’’ concentrations, the NNRTIs may be expected to effect a long-lasting suppression of HIV-1 replication This ‘‘knocking-out’’ phenomenon could be obtained at lower concentrations if the NNRTIs were combined with each other, or with any of the ddN analogues (i.e., AZT), particularly if selected on the basis of the ‘‘mutually counteracting mutation’’ principle VII CONCLUSION An acute HIV infection can be blocked at any of the following stages of the infection: virus adsorption, virus – cell fusion, viral uncoating, and reverse transcription At the reverse transcriptase (RT) level, chemotherapeutic intervention could be envisaged at either the substrate or a non – substrate binding site Polyanionic substances (i.e., sulfated polysaccharides) prevent virus adsorption; plant lectins, succinylated (or aconitylated) albumins, and triterpene (i.e., betulinic acid) derivatives interfere with virus – cell fusion; bicyclams inhibit viral uncoating; 2V,3V-dideoxynucleosides (ddNs) and acyclic nucleoside phosphonate analogues, following intracellular conversion to their phosphorylated derivatives, interact with the substrate binding site of the RT; and the nonnucleoside reverse transcriptase inhibitors (NNRTIs) are targeted at a non –substrate binding site of HIV-1 RT Some of these compounds (viz., bicyclams) and, among the NNRTIs, some of the HEPT and a-APA derivatives, were found to inhibit HIV-1 replication at concentrations (f1 ng/mL) that were 100,000-fold or more below the cytotoxicity threshold As a rule, it may be postulated that the more specific the antiviral action, the more likely the development of virus – drug resistance; hence, NNRTIs, which engage in a highly Copyright 2004 by Marcel Dekker, Inc All Rights Reserved specific interaction with HIV-1 RT, rapidly lead to the emergence of drugresistant virus strains To prevent such drug-resistant virus strains from emerging, several strategies could be envisaged, the most attractive being the combination of several drugs at concentrations high enough to ‘‘knock out’’ the virus from the start This ‘‘knocking-out’’ phenomenon has been achieved with the NNRTIs, regardless of whether combined with any of the ddN analogues, and it may be extended to combinations of drugs that interact at targets other than the reverse transcriptase ACKNOWLEDGMENTS The original investigations of the author are supported by the Biomedical Research Programme of the European Community, the Belgian Nationaal Fonds voor Wetenschappelijk Onderzoek, the Belgian Fonds voor Geneeskundig Wetenschappelijk Onderzoek, the Belgian Geconcerteerde Onderzoeksacties, and the Janssen Research Foundation I thank Christiane Callebaut for her dedicated editorial assistance REFERENCES De Clercq E New perspectives for the chemotherapy and chemoprophylaxis of AIDS (acquired immune deficiency syndrome) Verh K Acad Geneeskd Belg 1992; 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90:6952 – 6956 Kleim J-P, Bender R, Kirsch R, Meichsner C, Paessens A, Riess G Muta- Copyright 2004 by Marcel Dekker, Inc All Rights Reserved ... Cannabinergics: Old and New Possibilities Andreas Goutopoulos and Alexandros Makriyannis Development of PET and SPECT Radioligands for Cannabinoid Receptors S John Gatley, Andrew N Gifford, Yu-Shin... areas of research and will provide a contemporary picture of the overall field of drug discovery to scientists from diverse disciplines Alexandros Makriyannis Diane Biegel Copyright 2004 by Marcel... structure-based drug design has become an integral part of the modern drug discovery process and has begun to contribute to a significant portion of the current drug discovery portfolio Copyright 2004 by
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Xem thêm: Drug discovery strategies and methods 2004 makriyannis biegel , Drug discovery strategies and methods 2004 makriyannis biegel , III. THE STRUCTURE-BASED DRUG DESIGN CYCLE, D. MODEL BUILDING AND REFINEMENT, L. DEDICATED MOLECULAR BIOLOGY AND PROTEIN PURIFICATION GROUPS ARE ESSENTIAL, II. SRC TYROSINE KINASE AND OSTEOPOROSIS, III. SH2 DOMAINS AND PHOSPHOPEPTIDE BINDING, V. SOLID-PHASE PARALLEL SYNTHESIS AND NONPEPTIDE PHENYL PHOSPHATE LIBRARIES, VI. STRUCTURE-BASED, SMALL-MOLECULE LIBRARIES TO EXPLORE SRC SH2 BINDING, VII. DISCOVERY OF AN IN VIVO EFFECTIVE SRC SH2 INHIBITOR, II. THE MATRIX METALLOPROTEINASE FAMILY, III. ASSIGNMENT OF THE RESONANCES OF THE INHIBITED CATALYTIC DOMAIN OF STROMELYSIN-1, IV. ASSIGNMENT OF THE RESONANCES OF THE INHIBITOR AND NOES BETWEEN THE PROTEIN AND THE INHIBITOR, VI. STRUCTURE OF INHIBITED STROMELYSIN-1, VII. COMPARISON OF INHIBITED STROMELYSIN TO OTHER MMPS, V. MAJOR CLASSES OF CANNABINERGIC LIGANDS, VI. THERAPEUTIC POTENTIAL OF CANNABINERGIC AGENTS, III. ATTEMPTS TO DEVELOP RADIOLIGANDS, A. STRUCTURE–ACTIVITY STUDIES OF TIP(P) PEPTIDES, A. PROTOTYPES AND STRUCTURE–ACTIVITY RELATIONSHIPS, B. CONFORMATIONAL STUDY OF H-TYR-C[-ORN-2-NAL-DPRO-GLY-], II. RESINS AND LINKERS FOR CARBOXYLIC ACID GENERATION, III. RESINS AND LINKERS FOR GENERATION OF AMIDE FUNCTION, V. RESINS AND LINKERS FOR HYDROXYL AND GENERATION OF AMINO FUNCTION, IX. RESINS AND LINKERS FOR GENERATION OF OTHER FUNCTIONS, B. ALLOSTERIC MODULATION ON THE ADENOSINE RECEPTOR, I. DISEASES WITH PROTEIN MISFOLDING, III. INTERMEDIATES IN FIBRIL FORMATION, VI. CLINICAL TRIALS FOR AD TESTING OF POSSIBLE DISEASE-MODIFYING AGENTS, A. THE NATURE OF THE BINDING SITE, C. MODELING OF CONFORMATIONALLY RESTRICTED ANALOGUES, D. THE DEVELOPMENT OF A CLINICAL CANDIDATE, V. REVERSE TRANSCRIPTASE INHIBITORS INTERACTING WITH THE SUBSTRATE BINDING SITE, VI. REVERSE TRANSCRIPTASE INHIBITORS INTERACTING WITH A NONSUBSTRATE BINDING SITE: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

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