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| 作者简介： ROBERT A. COPELAND, PhD, is Department Head of Enzymology and Mechanistic Pharmacology at GlaxoSmithKline, and Adjunct Professor of Biochemistry and Biophysics at the University of Pennsylvania School of Medicine. Dr. Copeland has published more than 100 papers and reviews and has authored three books, including Enzymes: A Practical Introduction to Structure, Mechanism, and Data Analysis, Second Edition (Wiley). |
| Foreword Preface Acknowledgments 1.Why Enzymes as Drug Targets? 1.1 Enzymes Are Essentials for Life 1.2 Enzyme Structure and Catalysis 1.3 Permutations of Enzyme Structure During Catalysis 1.4 Other Reasons for Studying Enzymes 1.5 Summary References 2.Enzyme Reaction Mechanisms 2.1 Initial Binding of Substrate 2.2 Noncovalent Forces in Reversible Ligand Binding to Enzymes 2.2.1 Electrostatic Forces 2.2.2 Hydrogen Bonds 2.2.3 Hydrophobic Forces 2.2.4 van der Waals Forces 2.3 Transformations of the Bond Substrate 2.3.1 Strategies for Transition State Stabilization 2.3.2 Enzyme Active Sites Are Most Complementary to the Transition State Structure 2.4 Steady State Analysis of Enzyme Kinetics 2.4.1 Factors Affecting the Steady State Kinetic Constants 2.5 Graphical Determination of kcat and KM 2.6 Reactions Involving Multiple Substates 2.6.1 Bisubstrate Reaction Mechanisms 2.7 Summary References 3.Reversible Modes of Inhibitor Interactions with Enzymes 3.1 Enzyme-Inhibitor Binding Equilibria 3.2 Competitive Inhibition 3.3 Noncompetitive Inhibition 3.3.1 Mutual Exclusively Studies 3.4 Uncompetitive Inhibition 3.5 Inhibition Modality in Bisubstrate Reactions 3.6 Value of Knowing Inhibitor Modality 3.6.1 Quantitative Comparisons of Inhibitor Affinity 3.6.2 Relating Ki to Binding Energy 3.6.3 Defining Target Selectivity by Ki Values 3.6.4 Potential Advantages and Disadvantages of Different Inhibition Modalities In Vivo 3.6.5 Knowing Inhibition Modality Is Important for Structure-Based Lead Organization 3.7 Summary References 4.Assay Considerations for Compound Library Screening 4.1 Defining Inhibition Signal Robustness, and Hit Criteria 4.2 Measuring Initial Velocity 4.2.1 End-Point and Kinetic Readouts 4.2.2 Effects of Enzyme Concentration 4.3 Balanced Assay Conditions 4.3.1 Balancing Conditions for Multisubstrate Reactions 4.4 Order of Reagent Addition 4.5 Use of Natural Substrates and Enzymes 4.6 Coupled Enzyme Assays 4.7 Hit Validation and Progression 4.8 Summary References 5.Lead Optimization and Structure-Activity Relationships for Reversible Inhibitors 5.1 Concentration-Response Plots and IC50 Determination 5.1.1 The Hill Coefficient 5.1.2 Graphing and Reporting Concentration-Response Data 5.2 Testing for Reversibility 5.3 Determining Reversible Inhibition Modality and Dissociation Constant 5.4 Comparing Relative Affinity 5.4.1 Compound Selectivity 5.5 Associating Cellular Effects with Target Enzyme Inhibition 5.5.1 Cellular Phenotype Should Be Consistent with Genetic Knockout or Knockdown of the Target Enzyme 5.5.2 Cellular Activity Should Require a Certain Affinity for the target Enzyme 5.5.3 Buildup of Substrate and/or Diminution of Product for the Target Enzyme Should Be Observed in Cells 5.5.4 Cellular Phenotype Should Be Reversed by Cell-Permeable Product or Downstream Metabolites of the Target Enzyme Activity 5.5.5 Mutation of the Target Enzyme Should Lead to Resistance or Hypersensitivity to Inhibitors 5.6 Summary References 6.Slow Binding Inhibitors 7.Tight Binding Inhibitors 8.Irreversible Enzyme Inactivators Appendix 1.Kinetic of Biochemical Reactions A1.1 The Law of Mass Action and Reaction Order A1.2 First-Order Reaction Kinetics A1.3 Second-Order Reaction Kinetics A1.4 Pseudo-First-Order Reaction Conditions A1.5 Approach to Equilibrium: An Example of the Kinetics of Reversible Reactions References Appendix 2.Derivation of the Enzyme-Ligand Binding Isotherm Equation References Appendix 3.Serial Dilution Schemes Index |
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