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Ebook Burger’s medicinal chemistry and drug discovery (6/E): Part 2

Part 2 book “Burger’s medicinal chemistry and drug discovery” has contents: Structure - based drug design, electron cryomicroscopy of biological macromolecules, mass spectrometry and drug discovery, peptidomimetics for drug design, natural products as leads for new pharmaceuticals, and other cotents. | CHAPTER TEN Structure-Based Drug Design LARRY W. HARDY Aurigene Discovery Technologies Lexington, Massachusetts DONALD J. ABRAHAM Virginia Commonwealth University Richmond, Virginia MARTIN K. SAFO Virginia Commonwealth University Richmond, Virginia Contents 1 Introduction, 418 2 Structure-Based Drug Design, 419 2.1 Theory and Methods, 419 2.2 Hemoglobin, One of the First Drug-Design Targets, 419 2.2.1 History, 419 2.2.2 Sickle-Cell Anemia, 419 2.2.3 Allosteric Effectors, 421 2.2.4 Crosslinking Agents, 424 2.3 Antifolate Targets, 425 2.3.1 Dihydrofolate Reductase, 425 2.3.2 Thymidylate Synthase, 426 2.3.2.1 Structure-Guided Optimization: AG85 and AG337,426 2.3.2.2 De Novo Lead Generation: AG331,428 2.3.3 Glycinamide Ribonucleotide Formyltransferase, 429 2.4 Proteases, 432 2.4.1 Angiotensin-Converting Enzyme and the Discovery of Captopril, 432 2.4.2 HIV Protease, 433 2.4.3 Thrombin, 442 2.4.4 Caspase-1, 444 2.4.5 Matrix Metalloproteases, 445 2.5 Oxidoreductases, 446 2.5.1 Inosine Monophosphate Dehydrogenase, 447 2.5.2 Aldose Reductase, 448 2.6 Hydrolases, 449 2.6.1 Acetylcholinesterase, 449 2.6.2 Neuraminidase, 450 Burger's Medicinal Chemistry a n d Drug Discovery Sixth Edition, Volume 1: Drug Discovery Edited by Donald J. Abraham ISBN 0-471-27090-3 Q 2003 John Wiley & Sons, Inc. 417 Structure-Based Drug Design 2.6.3 Phospholipase A2 (Nonpancreatic, Secretory), 452 2.7 Picornavirus Uncoating, 454 2.8 Phosphoryl Transferases, 456 1 INTRODUCTION Structure-based drug design by use of structural biology remains one of the most logical and aesthetically pleasing approaches in drug discovery paradigms. The first paper on the potential use of crystallography in medicinal chemistry was written in 1974 (1)and was presented at Professor Alfred Burger's retirement symposium in 1972. The excerpted last paragraph in the paper, reproduced below, foresaw the integration of X-ray crystallography into the field of medicinal chemistry. It is reasonable to assume then that .