Evaluation Of Enzyme Inhibitors In Drug Discovery: A Guide For Medicinal Chemists And Pharmacologist药物发现中的酶抑制剂评估：医学药剂师与药物学家指南 mobi 下载 网盘 caj lrf pdf txt 阿里云

Vital information for discovering and optimizing new drugs

"Understanding the data and the experimental details that *** it has always been at the heart of good science and the assumption challenging process that leads from good science to drug discovery. This book helps medicinal chemists and pharmacologists to do exactly that in the realm of enzyme inhibitors."

-Paul S. Anderson, PhD

This publication provides readers with a thorough understanding of enzyme-inhibitor evaluation to assist them in their efforts to discover and optimize novel drug therapies. Key topics such as competitive, noncompetitive, and uncompetitive inhibition, slow binding, tight binding, and the use of Hill coefficients to study reaction stoichiometry are all presented. Examples of key concepts are presented with an emphasis on clinical relevance and practical applicati***.

Targeted to medicinal chemists and pharmacologists, Evaluation of Enzyme Inhibitors in Drug Discovery focuses on the questi*** that they need to address:

* What opportunities for inhibitor in***cti*** with enzyme targets arise from c***ideration of the catalytic reaction mechanism?

* How are inhibitors evaluated for potency, selectivity, and mode of action?

* What are the advantages and disadvantages of specific inhibition modalities with respect to efficacy in vivo?

* What information do medicinal chemists and pharmacologists need from their biochemistry and enzymology colleagues to effectively pursue lead optimization?

Beginning with a discussion of the advantages of enzymes as targets for drug discovery, the publication then explores the reaction mechanisms of enzyme catalysis and the types of in***cti*** that can occur between enzymes and inhibitory molecules that lend themselves to the***utic use. Next are discussi*** of mechanistic issues that must be c***idered when designing enzyme assays for compound library screening and for lead optimization efforts. Finally, the publication delves into special forms of inhibition that are commonly encountered in drug discovery efforts, but can be easily overlooked or misinterpreted.

This publication is designed to provide students with a solid foundation in enzymology and its role in drug discovery. Medicinal chemists and pharmacologists can refer to individual chapters as specific issues arise during the course of their ongoing drug discovery efforts.

Foreword

Preface

Acknowledgments

1.Why Enzymes as Drug Targets?

　1.1 Enzymes Are Essentials for Life

　1.2 Enzyme Structure and Catalysis

　1.3 Permutati*** of Enzyme Structure During Catalysis

　1.4 Other Reas*** 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 Transformati*** 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 C***tants

　2.5 Graphical Determination of kcat and KM

　2.6 Reacti*** Involving Multiple Substates

　　2.6.1 Bisubstrate Reaction Mechanisms

　2.7 Summary

　References

3.Reversible Modes of Inhibitor In***cti*** 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 Reacti***

　3.6 Value of Knowing Inhibitor Modality

　　3.6.1 Quantitative Comparis*** of Inhibitor Affinity

　　3.6.2 Relating Ki to Binding Energy

　　3.6.3 Defining Target Selectivity by Ki Values

　　3.*** 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 C***iderati*** 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 Conditi***

　　4.3.1 Balancing Conditi*** for Multisubstrate Reacti***

　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 Relati***hips for Reversible Inhibitors

　5.1 Concentration-Resp***e Plots and IC50 Determination

　　5.1.1 The Hill Coefficient

　　5.1.2 Graphing and Reporting Concentration-Resp***e Data

　5.2 Testing for Reversibility

　5.3 Determining Reversible Inhibition Modality and Dissociation C***tant

　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 C***istent 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 Reacti***

　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 Conditi***

　A1.5 Approach to Equilibrium: An Example of the Kinetics of Reversible Reacti***

References

Appendix 2.Derivation of the Enzyme-Ligand Binding Isotherm Equation

References

Appendix 3.Serial Dilution Schemes

Index

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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).

书籍介绍

Vital information for discovering and optimizing new drugs

"Understanding the data and the experimental details that *** it has always been at the heart of good science and the assumption challenging process that leads from good science to drug discovery. This book helps medicinal chemists and pharmacologists to do exactly that in the realm of enzyme inhibitors."

-Paul S. Anderson, PhD

This publication provides readers with a thorough understanding of enzyme-inhibitor evaluation to assist them in their efforts to discover and optimize novel drug therapies. Key topics such as competitive, noncompetitive, and uncompetitive inhibition, slow binding, tight binding, and the use of Hill coefficients to study reaction stoichiometry are all presented. Examples of key concepts are presented with an emphasis on clinical relevance and practical applicati***.

Targeted to medicinal chemists and pharmacologists, Evaluation of Enzyme Inhibitors in Drug Discovery focuses on the questi*** that they need to address:

* What opportunities for inhibitor in***cti*** with enzyme targets arise from c***ideration of the catalytic reaction mechanism?

* How are inhibitors evaluated for potency, selectivity, and mode of action?

* What are the advantages and disadvantages of specific inhibition modalities with respect to efficacy in vivo?

* What information do medicinal chemists and pharmacologists need from their biochemistry and enzymology colleagues to effectively pursue lead optimization?

Beginning with a discussion of the advantages of enzymes as targets for drug discovery, the publication then explores the reaction mechanisms of enzyme catalysis and the types of in***cti*** that can occur between enzymes and inhibitory molecules that lend themselves to the***utic use. Next are discussi*** of mechanistic issues that must be c***idered when designing enzyme assays for compound library screening and for lead optimization efforts. Finally, the publication delves into special forms of inhibition that are commonly encountered in drug discovery efforts, but can be easily overlooked or misinterpreted.

This publication is designed to provide students with a solid foundation in enzymology and its role in drug discovery. Medicinal chemists and pharmacologists can refer to individual chapters as specific issues arise during the course of their ongoing drug discovery efforts.