DRUG DESIGN: STRUCTURE- AND LIGAND-BASED …

1 drug design : structure - AND LIGAND-BASED APPROACHESS tructure-based drug design (SBDD) and LIGAND-BASED drug design (LBDD) are active areasof research in both the academic and commercial realms. This book provides a current snap-shot of the field of computer-aided drug design and associated experimental covered include x-ray crystallography, nuclear magnetic resonance, fragment-baseddrug design , free-energy methods, docking and scoring, linear-scaling quantum calcula-tions, quantitative structure /activity relationship, pharmacophore methods, computationalabsorption/distribution/met abolism/excretion-toxicity, and drug discovery case from academic and commercial institutions all over the world have contributed tothis book, which is illustrated with more than 200 images.

2 This book covers SBDD and LBDD,and it provides the most up-to-date information on a wide range of topics for the practicingcomputational chemist, medicinal chemist, or structural M. Merz, Jr., received his PhD in organic chemistry at the University of Texas at Austinand completed postdoctoral research at Cornell University and the University of California,San Francisco. He is a member of the Quantum Theory Project and Professor of Chemistry atthe University of Florida, Ringe received her PhD in biochemistry at Boston University. She is Professor of Bio-chemistry and Chemistry in the Rosenstiel Basic Medical Sciences Research Center at BrandeisUniversity, Waltham, H. Reynolds received his PhD in theoretical organic chemistry at the University ofTexas at Austin.

3 He is a Research Fellow at Johnson & Johnson Pharmaceutical Research andDevelopment, Spring House, in this web service Cambridge University PressCambridge University Press978-0-521-88723-6 - drug design : structure - and LIGAND-BASED ApproachesEdited by Kenneth M. Merz, Dagmar Ringe and Charles H. ReynoldsFrontmatterMore informationDrug DesignSTRUCTURE- AND LIGAND-BASEDAPPROACHESE dited byKenneth M. Merz, of Florida, GainesvilleDagmar RingeBrandeis University, Waltham, MassachusettsCharles H. ReynoldsJohnson & Johnson Pharmaceutical Research and Development,Spring House, in this web service Cambridge University PressCambridge University Press978-0-521-88723-6 - drug design : structure - and LIGAND-BASED ApproachesEdited by Kenneth M.

4 Merz, Dagmar Ringe and Charles H. ReynoldsFrontmatterMore informationcambridge university pressCambridge, New York, Melbourne, Madrid, Cape Town, Singapore,S ao Paulo, Delhi, Dubai, TokyoCambridge University Press32 Avenue of the Americas, New York, NY 10013-2473, on this title: Cambridge University Press 2010 This publication is in copyright. Subject to statutory exceptionand to the provisions of relevant collective licensing agreements,no reproduction of any part may take place without the writtenpermission of Cambridge University published 2010 Printed in China by EverbestA catalog record for this publication is available from the British of Congress Cataloging in Publication dataDrug design : structure - and LIGAND-BASED approaches / edited by Kenneth M.

5 Merz,Dagmar Ringe, Charles H. ; bibliographical references and 978-0-521-88723-6 (hardback)1. Drugs design . 2. Drugs STRUCTURE- activity relationships. I. Merz, Kenneth M., 1959 II. Ringe, Dagmar. III. Reynolds, Charles H., 1957 IV. Title.[DNLM: 1. drug design . 2. Ligands. 3. STRUCTURE- Activity 744 D79327 2010] 2010615 .19 dc222009051613 ISBN978-0-521-88723-6 HardbackCambridge University Press has no responsibility for the persistence oraccuracy ofURLs for external or third-party Internet Web sites referred to inthis publication and does not guarantee that any content on such Web sites is,or will remain, accurate or in this web service Cambridge University PressCambridge University Press978-0-521-88723-6 - drug design : structure - and LIGAND-BASED ApproachesEdited by Kenneth M.

6 Merz, Dagmar Ringe and Charles H. ReynoldsFrontmatterMore informationContentsContributorspageviiPr efaceix1 Progress and issues for computationally guided lead discovery and optimization1 William L. JorgensenPART I. STRUCTURAL BIOLOGY2 X-ray crystallography in the service of STRUCTURE- based drug design17 Gregory A. Petsko and Dagmar Ringe3 Fragment-based STRUCTURE- guided drug discovery: strategy, process, and lessonsfrom human protein kinases30 Stephen K. Burley, Gavin Hirst, Paul Sprengeler, and Siegfried Reich4 NMR in fragment-based drug discovery41 Christopher A. Lepre, Peter J. Connolly, and Jonathan M. MoorePART II. COMPUTATIONAL CHEMISTRY METHODOLOGY5 Free-energy calculations in STRUCTURE- based drug design61 Michael R.

7 Shirts, David L. Mobley, and Scott P. Brown6 studies of drug resistance and the dynamic behavior of HIV-1 protease throughmolecular dynamics simulations87 Fangyu Ding and Carlos Simmerling7 Docking: a domesday report98 Martha S. Head8 The role of quantum mechanics in STRUCTURE- based drug design120 Kenneth M. Merz, Pharmacophore methods137 Steven L. Dixon10 QSAR in drug discovery151 Alexander Tropsha11 Predicting ADME properties in drug discovery165 William J. in this web service Cambridge University PressCambridge University Press978-0-521-88723-6 - drug design : structure - and LIGAND-BASED ApproachesEdited by Kenneth M. Merz, Dagmar Ringe and Charles H.

8 ReynoldsFrontmatterMore informationviContentsPART III: APPLICATIONS TO drug DISCOVERY12 Computer-aided drug design : a practical guide to protein- STRUCTURE- based modeling181 Charles H. Reynolds13 STRUCTURE- based drug design case study: p38197 Arthur M. Doweyko14 STRUCTURE- based design of novel P2-P4 macrocyclic inhibitors of hepatitisC NS3/4A protease209M. Katharine Holloway and Nigel J. Liverton15 Purine nucleoside phosphorylases as targets for transition-state analog design215 Andrew S. Murkin and Vern L. Schramm16 GPCR 3D modeling248 Frank U. Axe17 STRUCTURE- based design of potent glycogen phosphorylase inhibitors257 Qiaolin in this web service Cambridge University PressCambridge University Press978-0-521-88723-6 - drug design : structure - and LIGAND-BASED ApproachesEdited by Kenneth M.

9 Merz, Dagmar Ringe and Charles H. ReynoldsFrontmatterMore informationContributorsFrank U. AxeAxe Consulting ServicesSutter Creek, CaliforniaScott P. BrownDepartment of Structural BiologyAbbott LaboratoriesAbbott Park, IllinoisStephen K. BurleySGX PharmaceuticalsSan Diego, CaliforniaPeter J. ConnollyVertex Pharmaceuticals , MassachusettsQiaolin DengDepartment of Molecular SystemsMerck Research LaboratoriesMerck & Co. , New JerseyFangyu DingDepartment of ChemistryCenter for Structural BiologyStony Brook UniversityStony Brook, New YorkSteven L. DixonSchrodinger, York, New YorkArthur M. DoweykoResearch and DevelopmentComputer-Assisted drug DesignBristol-Myers SquibbPrinceton, New JerseyWilliam J.

10 EganNovartis Institutes for BioMedical ResearchCambridge, MassachusettsMartha S. HeadComputational and Structural ChemistryGlaxoSmithKline PharmaceuticalsCollegeville, PennsylvaniaGavin HirstSGX PharmaceuticalsSan Diego, CaliforniaM. Katharine HollowayMolecular SystemsMerck Research LaboratoriesWest Point, PennsylvaniaWilliam L. JorgensenDepartment of ChemistryYale UniversityNew Haven, ConnecticutChristopher A. LepreVertex Pharmaceuticals , MassachusettsNigel J. LivertonMedicinal ChemistryMerck Research LaboratoriesWest Point, PennsylvaniaKenneth M. Merz, of Chemistry andQuantum Theory ProjectUniversity of FloridaGainesville, FloridaDavid L. MobleyDepartment of ChemistryUniversity of New OrleansNew Orleans, LouisianaJonathan M.