Evaluation of Enzyme Inhibitors in Drug Discovery A Guide for Medicinal Chemists and Pharmacologists

ISBN-10: 0471686964

ISBN-13: 9780471686965

Edition: 2005

List price: $142.00
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Description:

The goal of this book is to provide chemists & pharmacologists with the key information they need to answer questions about inhibitor interactions, inhibitor evaluations, the potential advantages & disadvantages of specific inhibition modalities with respect to efficacy in vivo, & much more.
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Book details

List price: $142.00
Copyright year: 2005
Publisher: John Wiley & Sons, Incorporated
Publication date: 3/28/2005
Binding: Hardcover
Pages: 296
Size: 6.25" wide x 9.25" long x 0.75" tall
Weight: 1.144
Language: English

Foreword
Preface
Acknowledgments
Why Enzymes as Drug Targets?
Enzymes Are Essentials for Life
Enzyme Structure and Catalysis
Permutations of Enzyme Structure During Catalysis
Other Reasons for Studying Enzymes
Summary
References
Enzyme Reaction Mechanisms
Initial Binding of Substrate
Noncovalent Forces in Reversible Ligand Binding to Enzymes
Electrostatic Forces
Hydrogen Bonds
Hydrophobic Forces
van der Waals Forces
Transformations of the Bond Substrate
Strategies for Transition State Stabilization
Enzyme Active Sites Are Most Complementary to the Transition State Structure
Steady State Analysis of Enzyme Kinetics
Factors Affecting the Steady State Kinetic Constants
Graphical Determination ofk cat and K M
Reactions Involving Multiple Substates
Bisubstrate Reaction Mechanisms
Summary
References
Reversible Modes of Inhibitor Interactions with Enzymes
Enzyme-Inhibitor Binding Equilibria
Competitive Inhibition
Noncompetitive Inhibition
Mutual Exclusively Studies
Uncompetitive Inhibition
Inhibition Modality in Bisubstrate Reactions
Value of Knowing Inhibitor Modality
Quantitative Comparisons of Inhibitor Affinity
RelatingK i to Binding Energy
Defining Target Selectivity byK i Values
Potential Advantages and Disadvantages of Different Inhibition Modalities In Vivo
Knowing Inhibition Modality Is Important for Structure-Based Lead Organization
Summary
References
Assay Considerations for Compound Library Screening
Defining Inhibition Signal Robustness, and Hit Criteria
Measuring Initial Velocity
End-Point and Kinetic Readouts
Effects of Enzyme Concentration
Balanced Assay Conditions
Balancing Conditions for Multisubstrate Reactions
Order of Reagent Addition
Use of Natural Substrates and Enzymes
Coupled Enzyme Assays
Hit Validation and Progression
Summary
References
Lead Optimization and Structure-Activity Relationships for Reversible Inhibitors
Concentration-Response Plots and IC 50 Determination
The Hill Coefficient
Graphing and Reporting Concentration-Response Data
Testing for Reversibility
Determining Reversible Inhibition Modality and Dissociation Constant
Comparing Relative Affinity
Compound Selectivity
Associating Cellular Effects with Target Enzyme Inhibition
Cellular Phenotype Should Be Consistent with Genetic Knockout or Knockdown of the Target Enzyme
Cellular Activity Should Require a Certain Affinity for the target Enzyme
Buildup of Substrate and/or Diminution of Product for the Target Enzyme Should Be Observed in Cells
Cellular Phenotype Should Be Reversed by Cell-Permeable Product or Downstream Metabolites of the Target Enzyme Activity
Mutation of the Target Enzyme Should Lead to Resistance or Hypersensitivity to Inhibitors
Summary
References
Slow Binding Inhibitors
Determiningk obs : The Rate Constant for Onset of Inhibition
Mechanisms of Slow Binding Inhibition
Determination of Mechanism and Assessment of True Affinity
Potential Clinical Advantages of Slow Off-rate Inhibitors
Determining Inhibition Modality for Slow Binding Inhibitors
SAR for Slow Binding Inhibitors
Some Examples of Pharmacologically Interes
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