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MEDICINAL CHEMISTRY AND DRUG DISCOVERY Sixth Edition Volume 1: Drug Discovery Edited by Donald J.A braham Department of Medicinal Chemistry . . School of Pharmacy Vir - r iversity - m Burger's Medicinal Chemistry and Drug Discovery is available Online in full color at www.mrw.interscience.wiley.com/bmcdd. A John Wiley and Sons, Inc., Publication BURGER MEMORIAL EDITION The Sixth Edition of Burger's Medicinal laboratories, brought to market [Parnate, Chemistry and Drug Discovery is being desig- which is the brand name for tranylcypromine, nated as a Memorial Edition. Professor Alfred a monoamine oxidase (MAO) inhibitor]. Dr. Burger was born in Vienna, Austria on Sep- Burger was a visiting Professor at the Univer- tember 6, 1905 and died on December 30, sity of Hawaii and lectured throughout the 2000. Dr. Burger received his Ph.D. from the world. He founded the Journal of Medicinal University of Vienna in 1928 and joined the Chemistry, Medicinal Chemistry Research, Drug Addiction Laboratory in the Department and published the first major reference work of Chemistry at the University of Virginia in "Medicinal Chemistry" in two volumes in 1929. During his early years at UVA, he syn- 1951. His last published work, a book, was thesized fragments of the morphine molecule written at age 90 (Understanding Medica- in an attempt to find the analgesic pharma- tions: What the Label Doesn't Tell You, June cophore. He joined the UVA chemistry faculty 1995). Dr. Burger received the Louis Pasteur in 1938 and served the department until his Medal of the Pasteur Institute and the Amer, retirement in 1970. The chemistry depart- ican Chemical Society Smissman Award. Dr. ment at UVA became the major academic Burger played the violin and loved classical training ground for medicinal chemists be- music. He was married for 65 years to Frances cause of Professor Burger. Page Burger, a genteel Virginia lady who al- Dr. Burger's research focused on analge- ways had a smile and an open house for the sics, antidepressants, and chemotherapeutic Professor's graduate students and postdoc- agents. He is one of the few academicians to toral fellows. have a drug, designed and synthesized in his vii PREFACE The Editors, Editorial Board Members, and sixth edition, we devote an entire subsection John Wiley and Sons have worked for three of Volume 4 to cancer research; we have also and a half years to update the fifth edition of reviewed the major published Medicinal Burger's Medicinal Chemistry and Drug Dis- Chemistry and Pharmacology texts to ensure covery. The sixth edition has several new and that we did not omit any major therapeutic unique features. For the first time, there will classes of drugs. An editorial board was consti- be an online version of this major reference tuted for the first time to also review and sug- work. The online version will permit updating gest topics for inclusion. Their help was and easy access. For the first time, all volumes greatly appreciated. The newest innovation in are structured entirely according to content this series will be the publication of an aca- and published simultaneously. Our intention demic, "textbook-like" version titled, "Bur- was to provide a spectrum of fields that would ger's Fundamentals of Medicinal Chemistry." provide new or experienced medicinal chem- The academic text is to be published about a ists, biologists, pharmacologists and molecu- year after this reference work appears. It will lar biologists entry to their subjects of interest also appear with soft cover. Appropriate and as well as provide a current and global per- key information will be extracted from the ma- spective of drug design, and drug develop- jor reference. ment. There are numerous colleagues, friends, Our hope was to make this edition of and associates to thank for their assistance. Burger the most comprehensive and useful First and foremost is Assistant Editor Dr. published to date. To accomplish this goal, we John Andrako, Professor emeritus, Virginia expanded the content from 69 chapters (5 vol- Commonwealth University, School of Phar- umes) by approximately 50% (to over 100 macy. John and I met almost every Tuesday chapters in 6 volumes). We are greatly in debt for over three years to map out and execute to the authors and editorial board members the game plan for the sixth edition. His contri- participating in this revision of the major ref- bution to the sixth edition cannot be under- erence work in our field. Several new subject stated. Ms. Susanne Steitz, Editorial Program areas have emerged since the fifth edition ap- Coordinator at Wiley, tirelessly and meticu- peared. Proteomics, genomics, bioinformatics, lously kept us on schedule. Her contribution combinatorial chemistry, high-throughput was also key in helping encourage authors to screening, blood substitutes, allosteric effec- return manuscripts and revisions so we could tors as potential drugs, COX inhibitors, the publish the entire set at once. I would also like statins, and high-throughput pharmacology to especially thank colleagues who attended are only a few. In addition to the new areas, we the QSAR Gordon Conference in 1999 for very have filled in gaps in the fifth edition by in- helpful suggestions, especially Roy Vaz, John cluding topics that were not covered. In the Mason, Yvonne Martin, John Block, and Hugo Preface Kubinyi. The editors are greatly indebted to Dukat, Martin Safo, Jason Rife, Kevin Reyn- Professor Peter Ruenitz for preparing a tem- olds, and John Andrako in our Department plate chapter as a guide for all authors. My of Medicinal Chemistry, School of Pharmacy, secretary, Michelle Craighead, deserves spe- Virginia Commonwealth University for sug- cial thanks for helping contact authors and gestions and special assistance in reviewing reading the several thousand e-mails gener- manuscripts and text. Graduate student ated during the project. I also thank the com- Derek Cashman took able charge of our web puter center at Virginia Commonwealth Uni- site, http:l/www.burgersmedchem.com, an- versity for suspending rules on storage and other first for this reference work. I would es- e-mail so that we might safely store all the pecially like to thank my dean, Victor versions of the author's manuscri~tsw here Yanchick, and Virginia Commonwealth Uni- they could be backed up daily. ~ r $atn d not versity for their support and encouragement. least, I want to thank each and every author, Finally, I thank my wife Nancy who under- some of whom tackled two chapters. Their stood the magnitude of this project and pro- contributions have ~rovidedo ur-field with a vided insight on how to set up our home office A sound foundation of information to build for as well as provide John Andrako and me the future. We thank the many reviewers of lunchtime menus where we often dreamed of manuscripts whose critiques have greatly en- getting chapters completed in all areas we se- hanced the presentation and content for the lected. To everyone involved, many, many sixth edition. Special thanks to Professors thanks. Richard Glennon, William Soine, Richard Westkaemper, Umesh Desai, Glen Kel- D J. A ONALD BRAHAM logg, Brad Windle, Lemont Kier, Malgorzata Midlothian, Virginia Dr. Alfred Burger Pho ltograph of Professor Burger followed by his comments to the American Chemical Society 26th Medicinal Che ,mistry Symposium on June 14, 1998. This was his last public appearance at a meeting of medicinal cheim ists. As general chair of the 1998 ACS Medicinal Chemistry Symposium, the editor invited Professor Bur ger to open the meeting. He was concerned that the young chemists would not know who he was and he mig ht have an attack due to his battle with Parkinson's disease. These fears never were realized and his com .ments to the more than five hundred attendees drew a sustained standing ovation. The Professor was 93, and it was Mrs. Burger's 91st birthday. Opening Remarks ACS 26th Medicinal Chemistry Symposium June 14, 1998 Alfred Burger University of Virginia It has been 46 years since the third Medicinal Chemistry Symposium met at the University of Virginia in Charlottesville in 1952. Today, the Virginia Commonwealth University welcomes you and joins all of you in looking forward to an exciting program. So many aspects of medicinal chemistry have changed in that half century that most of the new data to be presented this week would have been unexpected and unbelievable had they been mentioned in 1952. The upsurge in biochemical understandings of drug transport and drug action has made rational drug design a reality in many therapeutic areas and has made medicinal chemistry an independent science. We have our own journal, the best in the world, whose articles comprise all the innovations of medicinal researches. And if you look at the announcements of job opportunities in the pharmaceutical industry as they appear in Chemical & Engineering News, you will find in every issue more openings in medicinal chemistry than in other fields of chemistry. Thus, we can feel the excitement of being part of this medicinal tidal wave, which has also been fed by the expansion of the needed research training provided by increasing numbers of universities. The ultimate beneficiary of scientific advances in discovering new and better therapeutic agents and understanding their modes of action is the patient. Physicians now can safely look . forward to new methods of treatment of hitherto untreatable conditions. To the medicinal scientist all this has increased the pride of belonging to a profession which can offer predictable intellectual rewards. Our symposium will be an integral part of these developments. xii CONTENTS HISTORY OF QUANTITATIVE DRUG-TARGET BINDING STRUCTURE-ACTMTY FORCES: ADVANCES IN FORCE RELATIONSHIPS, 1 FIELD APPROACHES, 169 C. D. Selassie Peter A. Kollman Chemistry Department University of California Pomona College School of Pharmacy Claremont, California Department of Pharmaceutical Chemistry San Francisco, California RECENT TRENDS IN QUANTITATrVE STRUCTURE- David A. Case ACTMTY RELATIONSHIPS, 49 The Scripps Research Institute . Department of Molecular Biology A. Tropsha La Jolla, California University of North Carolina Laboratory for Molecular Modeling School of Pharmacy COMBINATORIAL LIBRARY Chapel Hill, North Carolina DESIGN, MOLECULAR SIMILARITY, AND DIVERSITY APPLICATIONS, 187 MOLECULAR, MODELING IN DRUG DESIGN, 77 Jonathan S. Mason Pfizer Global Research & Garland R. Marshall Development Washington University Sandwich, United Kingdom Center for Computational Biology St. Louis, Missouri Stephen D. Pickett GlmoSmithKline Research Denise D. Beusen Stevenage, United Kingdom Tripos, Inc. St. Louis, Missouri xiii Contents xiv 6 VIRTUAL SCREENING, 243 Donald J. Abraham Virginia Commonwealth University Ingo Muegge Richmond, Virginia Istvan Enyedy Bayer Research Center West Haven, Connecticut 11 X-RAY CRYSTALLOGRAPHY IN DRUG DISCOVERY, 471 7 DOCKING AND SCORING Douglas A. Livingston FUNCTIONS/VIRTUAL Sean G. Buchanan SCREENING, 281 Kevin L. D'Amico Christoph Sotriffer Michael V. Milburn Gerhard Klebe Thomas S. Peat University of Marburg J. Michael Sauder Department of Pharmaceutical Structural GenomiX Chemistry San Diego, California Marburg, Germany Martin Stahl 12 NMR AND DRUG DISCOVERY, Hans-Joachim Bohm 507 Discovery Technologies F. Hoffmann-La Roche AG David J. Craik Basel, Switzerland Richard J. Clark Institute for Molecular Bioscience Australian Research Council 8 BIOINFORMATICS: ITS ROLE IN DRUG DISCOVERY, 333 Special Research Centre for Functional and Applied Genomics David J. ParrySmith . University of Queensland ChiBio Informatics Brisbane, Australia Cambridge, United Kingdom 9 CHEMICAL INFORMATION 13 MASS SPECTROMETRY AND COMPUTING SYSTEMS IN DRUG DISCOVERY, 583 DRUG DISCOVERY, 357 Richard B. van Breemen Douglas R. Henry Department of Medicinal Chemistry MDL Information Systems, Inc. and Pharmacognosy San Leandro, California University of Illinois at Chicago Chicago, Illinois 10 STRUCTURE-BASED DRUG DESIGN, 417 14 ELECTRON CRYOMICROSCOPY Larry W. Hardy OF BIOLOGICAL Aurigene Discovery Technologies MACROMOLECULES, 611 Lexington, Massachusetts Richard Henderson Martin K. Safo Medical Research Council Virginia Commonwealth University Laboratory of Molecular Biology Richmond, Virginia Cambridge, United Kingdom Contents Timothy S. Baker 19 STRUCTURAL CONCEPTS IN Purdue University THE PREDICTION OF THE Department of Biological Sciences TOXICITY OF THERAPEUTICAL West Lafayette, Indiana AGENTS, 827 Herbert S. Rosenkranz 15 PEPTIDOMIMETICS FOR DRUG Department of Biomedical Sciences DESIGN, 633 Florida Atlantic University Boca Raton, Florida M. Angels Estiarte Daniel H. Rich School of Pharmacy-Department of 20 NATURAL PRODUCTS AS Chemistry LEADS FOR NEW University of Wisconsin-Madison PHARMACEUTICALS, 847 Madison, Wisconsin A. D. Buss MerLion Pharmaceuticals 16 ANALOG DESIGN, 687 Singapore Science Park, Joseph G. Cannon Singapore The University of Iowa B. Cox Iowa City, Iowa Medicinal Chemistry Respiratory Diseases Therapeutic 17 APPROACHES TO THE Area RATIONAL DESIGN OF Novartis Pharma Research Centre ENZYME INHIBITORS, 715 Horsham, United Kingdom Michael J. McLeish R. D. Waigh . George L. Kenyon Department of Pharmaceutical Department of Medicinal Chemistry Sciences University of Michigan University of Strathclyde Ann Arbor, Michigan Glasgow, Scotland 18 CHIRALITY AND BIOLOGICAL INDEX, 901 ACTIVITY, 781 Alistair G. Draffan Graham R. Evans James A. Henshilwood Celltech R&D Ltd. Granta Park, Great Abington, Cambridge, United Kingdom
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