Evaluation of Enzyme Inhibitors in Drug Discovery - 2nd ed - A Guide for Medicinal Chemists and Pharmacologists

Informationen zum Autor ROBERT A. COPELAND, PhD, is Executive Vice President and Chief Scientific Officer at Epizyme, Inc., a biopharmaceutical company in Cambridge, Massachusetts. He is on the Editorial Board of The Journal of Biological Chemistry and a member of the Faculty of 1000. Dr. Copeland has contributed more than 175 publications to the scientific literature and holds eight U.S.-issued patents. He has authored several books in protein science and enzymology, including Enzymes: A Practical Introduction to Structure, Mechanism, and Data Analysis, Second Edition (Wiley). Klappentext Offers essential guidance for discovering and optimizing novel drug therapiesUsing detailed examples, Evaluation of Enzyme Inhibitors in Drug Discovery equips researchers with the tools needed to apply the science of enzymology and biochemistry to the discovery, optimization, and preclinical development of drugs that work by inhibiting specific enzyme targets. Readers will applaud this book for its clear and practical presentations, including its expert advice on best practices to follow and pitfalls to avoid.This Second Edition brings the book thoroughly up to date with the latest research findings and practices. Updates explore additional forms of enzyme inhibition and special treatments for enzymes that act on macromolecular substrates. Readers will also find new discussions detailing the development and application of the concept of drug-target residence time.Evaluation of Enzyme Inhibitors in Drug Discovery begins by explaining why enzymes are such important drug targets and then examines enzyme reaction mechanisms. The book covers:* Reversible modes of inhibitor interactions with enzymes* Assay considerations for compound library screening* Lead optimization and structure-activity relationships for reversible inhibitors* Slow binding and tight binding inhibitors* Drug-target residence time* Irreversible enzyme inactivatorsThe book ends with a new chapter exploring the application of quantitative biochemical principles to the pharmacologic evaluation of drug candidates during lead optimization and preclinical development.The Second Edition of Evaluation of Enzyme Inhibitors in Drug Discovery continues to offer a treatment of enzymology applied to drug discovery that is quantitative and mathematically rigorous. At the same time, the clear and simple presentations demystify the complex science of enzymology, making the book accessible to many fields- from pharmacology to medicinal chemistry to biophysics to clinical medicine. Zusammenfassung With enzymes being the most valued and common of drug targets, an understanding of their interactions with inhibitors is critical to successful drug discovery. Inhaltsverzeichnis Foreword to Second Edition xvii Christopher T. Walsh Preface to Second Edition xix Foreword to First Edition xxiii Paul S. Anderson Preface to First Edition xxv Acknowledgments from First Edition xxix 1. Why Enzymes as Drug Targets? 1 Key Learning Points 1 1.1 Enzymes Are Essential for Life 2 1.2 Enzyme Structure and Catalysis 6 1.3 Permutations of Enzyme Structure During Catalysis 12 1.4 Extension to Other Target Classes 17 1.5 Other Reasons for Studying Enzymes 18 1.6 Summary 21 References 22 2. Enzyme Reaction Mechanisms 25 Key Learning Points 25 2.1 Initial Binding of Substrate 25 2.2 Noncovalent Forces in Reversible Ligand Binding to Enzymes 28 2.2.1 Electrostatic Forces 28 2.2.2 Hydrogen Bonds 28 2.2.3 Hydrophobic Forces 29 2.2.4 Van der Waals Forces 30 2.3 Transformations of the Bound Substrate 30 2.3.1 Strategies for Transition State Stabilization 32 2.3.2 Enzyme Active Sites Are Most Complementary to the Transition State Str...

List of contents

FOREWORD TO SECOND EDITION BY CHRISTOPHER T. WALSH xvii
 
PREFACE TO SECOND EDITION xix
 
FOREWORD TO FIRST EDITION BY PAUL S. ANDERSON xxiii
 
PREFACE TO FIRST EDITION xxv
 
ACKNOWLEDGMENTS FROM FIRST EDITION xxix
 
1. WHY ENZYMES AS DRUG TARGETS? 1
 
Key Learning Points / 1
 
1.1 Enzymes Are Essential for Life / 2
 
1.2 Enzyme Structure and Catalysis / 6
 
1.3 Permutations of Enzyme Structure During Catalysis / 12
 
1.4 Extension to Other Target Classes / 17
 
1.5 Other Reasons for Studying Enzymes / 18
 
1.6 Summary / 21
 
References / 22
 
2. ENZYME REACTION MECHANISMS 25
 
Key Learning Points / 25
 
2.1 Initial Binding of Substrate / 25
 
2.2 Noncovalent Forces in Reversible Ligand Binding to Enzymes / 28
 
2.3 Transformations of the Bound Substrate / 30
 
2.4 Steady State Analysis of Enzyme Kinetics / 39
 
2.5 Typical Values of Steady State Kinetic Parameters / 46
 
2.6 Graphical Determination of kcat and KM / 47
 
2.7 Reactions Involving Multiple Substrates / 49
 
2.8 Summary / 54
 
References / 54
 
3. REVERSIBLE MODES OF INHIBITOR INTERACTIONS WITH ENZYMES 57
 
Key Learning Points / 57
 
3.1 Enzyme-Inhibitor Binding Equilibria / 58
 
3.2 Competitive Inhibition / 59
 
3.3 Noncompetitive Inhibition / 68
 
3.4 Uncompetitive Inhibition / 82
 
3.5 Inhibition Modality in Bisubstrate Reactions / 86
 
3.6 Value of Knowing Inhibitor Modality / 88
 
3.7 Enzyme Reactions on Macromolecular Substrates / 96
 
3.8 Summary / 118
 
References / 119
 
4. ASSAY CONSIDERATIONS FOR COMPOUND LIBRARY SCREENING 123
 
Key Learning Points / 123
 
4.1 Measures of Assay Performance / 125
 
4.2 Measuring Initial Velocity / 133
 
4.3 Balanced Assay Conditions / 142
 
4.4 Order of Reagent Addition / 146
 
4.5 Use of Natural Substrates and Enzymes / 148
 
4.6 Coupled Enzyme Assays / 154
 
4.7 Hit Validation / 156
 
4.8 Summary / 166
 
References / 166
 
5. LEAD OPTIMIZATION AND STRUCTURE-ACTIVITY RELATIONSHIPS FOR REVERSIBLE INHIBITORS 169
 
Key Learning Points / 169
 
5.1 Concentration-Response Plots and IC50 Determination / 170
 
5.2 Testing for Reversibility / 183
 
5.3 Determining Reversible Inhibition Modality and Dissociation Constant / 188
 
5.4 Comparing Relative Affinity / 190
 
5.5 Associating Cellular Effects with Target Enzyme Inhibition / 193
 
5.6 Summary / 200
 
References / 200
 
6. SLOW BINDING INHIBITORS 203
 
Key Learning Points / 203
 
6.1 Determining kobs: The Rate Constant for Onset of Inhibition / 205
 
6.2 Mechanisms of Slow Binding Inhibition / 207
 
6.3 Determination of Mechanism and Assessment of True Affi nity / 210
 
6.4 Determining Inhibition Modality for Slow Binding Inhibitors / 217
 
6.5 SAR for Slow Binding Inhibitors / 219
 
6.6 Some Examples of Pharmacologically Interesting Slow Binding Inhibitors / 220
 
6.7 Summary / 242
 
References / 243
 
7. TIGHT BINDING INHIBITION 245
 
Key Learning Points / 245
 
7.1 Effects of Tight Binding Inhibition on Concentration-Response Data / 246
 
7.2 The IC50 Value Depends on Ki app and [E]T / 248
 
7.3 Morrison's Quadratic Equation for Fitting Concentration-Response Data for Tight Binding Inhibitors / 253
 
7.4 Determining Modality for Tight Binding Enzyme Inhibitors / 258
 
7.5 Tight Binding Inhibito

Product details

• Authors: Copeland, Robert A Copeland, Robert A. Copeland
• Publisher: Wiley, John and Sons Ltd
• Languages: English
• Product format: Hardback
• Released: 16.04.2013
• EAN: 9781118488133
• ISBN: 978-1-118-48813-3
• No. of pages: 538
• Dimensions: 162 mm x 241 mm x 35 mm
• Subjects: Natural sciences, medicine, IT, technology > Medicine > Pharmacy; Chemie, Medizin, Enzyme, Wirkstoffforschung, chemistry, Pharmacology & Pharmaceutical Medicine, Pharmakologie u. Pharmazeutische Medizin, Wirkstoffforschung u. -entwicklung, Drug Discovery & Development, Medical Science, Enzyme u. Rezeptoren, Enzymes & Receptors