عنوان
پدید آورنده
موضوع
رده
QP601.5 .C675 2013
QP601
.
5
.
C675
2013
کتابخانه
محل استقرار
INTERNATIONAL STANDARD BOOK NUMBER
(Number (ISBN
111848813X
(Number (ISBN
1118540298
(Number (ISBN
9781118488133
(Number (ISBN
9781118540299
NATIONAL BIBLIOGRAPHY NUMBER
Country Code
bnb
Number
b429318
TITLE AND STATEMENT OF RESPONSIBILITY
Title Proper
Evaluation of enzyme inhibitors in drug discovery :
General Material Designation
[Book]
Other Title Information
a guide for medicinal chemists and pharmacologists /
First Statement of Responsibility
Robert A. Copeland
EDITION STATEMENT
Edition Statement
2nd ed
.PUBLICATION, DISTRIBUTION, ETC
Place of Publication, Distribution, etc.
Hoboken, N.J. :
Name of Publisher, Distributor, etc.
Wiley,
Date of Publication, Distribution, etc.
©2013
PHYSICAL DESCRIPTION
Specific Material Designation and Extent of Item
xxx, 538 pages :
Other Physical Details
illustrations ;
Dimensions
24 cm
GENERAL NOTES
Text of Note
Machine generated contents note: 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 KM2.6 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. 6.1 Determining kobs: The Rate Constant for Onset of Inhibition. 6.2 Mechanisms of Slow Binding Inhibition. 6.3 Determination of Mechanism and Assessment of True Affinity. 6.3.1 Potential Clinical Advantages of Slow Off-rate Inhibitors. 6.4 Determining Inhibition Modality for Slow Binding Inhibitors. 6.5 SAR for Slow Binding Inhibitors. 6.6 Some Examples of Pharmacologically Interesting Slow Binding Inhibitors. 6.6.1 Examples of Scheme B: Inhibitors of Zinc Peptidases and Proteases. 6.6.2 Example of Scheme C: Inhibition of Dihydrofolate Reductase by Methotresate. 6.6.3 Example of Scheme C: Inhibition of Calcineurin by FKBP-Inhibitor Complexes. 6.6.4 Example of Scheme C When Ki* <
INTERNAL BIBLIOGRAPHIES/INDEXES NOTE
Text of Note
Includes bibliographical references and index
CONTENTS NOTE
Text of Note
Why enzymes as drug targets? -- Enzyme reaction mechanisms -- Reversible modes of inhibitor interactions with enzymes -- Assay considerations for compound library screening -- Lead optimization and structure-activity relationships for reversible inhibitors -- Slow binding inhibitors -- Tight binding inhibition -- Drug-target residence time -- Irreversible enzyme inactivators -- Quantitative biochemistry in the pharmacological evaluation of drugs -- Appendix 1. Kinetics of biochemical reactions -- Appendix 2. Derivation of the enzyme-ligand binding isotherm equation -- Appendix 3. Serial dilution schemes -- Appendix 4. Relationship between [I]/IC50 and percentage inhibition of enzyme activity when h=1 -- Appendix 5. Propagation of uncertainties in experimental measurements -- Appendix 6. Useful physical constants at different temperatures -- Appendix 7. Common radioactive isotopes used in studies of enzymes -- Appendix 8. Common prefixes for units in biochemistry -- Appendix 9. Some aromatic ring systems commonly found in drugs -- Appendix 10. Residual plots
0
SUMMARY OR ABSTRACT
Text of Note
"There has been explosive growth in the hunt for new pharmaceutically agents globally. Traditionally, this has been the purview of the pharmaceutical industry, but today, this effort crosses academic, government, and industry laboratories across the world. Enzymes remain the most valued and common of drug targets; hence, a detailed understanding of their interactions with inhibitors is critical to successful drug discovery. This book provides a practical, readable, and comprehensive treatment of these topics that allows scientists to master the art of applied enzymology for drug discovery. The book addresses the opportunities for inhibitor interactions with enzyme targets arising from consideration of the catalytic reaction mechanism; discusses how inhibitors are properly evaluated for potency, selectivity, and mode of action, covers the potential advantages and liabilities of specific inhibition modalities with respect to efficacy in vivo, and provides valuable biochemical insights to help medicinal chemists and pharmacologists most effectively pursue lead optimization. It includes two new chapters, one on the pioneering idea of drug-target residence time fostered by Dr. Copeland, and the second on quantitative biochemistry. Five new appendices are added"--Provided by publisher
OTHER EDITION IN ANOTHER MEDIUM
Title
Evaluation of enzyme inhibitors in drug discovery.
International Standard Book Number
9781118540404
TOPICAL NAME USED AS SUBJECT
Drugs-- Design
Enzyme inhibitors-- Structure-activity relationships
Enzyme inhibitors-- Therapeutic use-- Testing
Drug Design
Enzyme Inhibitors-- chemistry
Enzyme Inhibitors-- therapeutic use
LIBRARY OF CONGRESS CLASSIFICATION
Class number
QP601
.
5
Class number
QP601
.
5
Book number
.
C675
2013
Book number
.
C675
2013
PERSONAL NAME - PRIMARY RESPONSIBILITY
Copeland, Robert Allen
ORIGINATING SOURCE
Date of Transaction
20170703092737.0
ELECTRONIC LOCATION AND ACCESS
Electronic name
مطالعه متن کتاب [Book]
Y
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