rdf-syntax-grammar
mods:
  schema location: http://www.loc.gov/mods/v3 http://www.loc.gov/standards/mods/v3/mods-3-2.xsd
  title info:
    title: Evaluation of enzyme inhibitors in drug discovery
    sub title: a guide for medicinal chemists and pharmacologists
  name:
    name part: Copeland, Robert Allen.
    role:
      role term: creator
  type of resource: text
  genre: bibliography
  genre: Electronic books.
  origin info:
    place:
      place term: nju
    place:
      place term: Hoboken, N.J
    publisher: Wiley
    date issued: ©2013
    date issued: 2013
    edition: 2nd ed.
    issuance: monographic
  language:
    language term: eng
  physical description:
    form: remote
    extent: 1 online resource
  abstract: "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.
  table of contents: Machine generated contents note: 1. Why Enzymes As Drug Targets? -- Key Learning Points -- 1.1. Enzymes Are Essential for Life -- 1.2. Enzyme Structure and Catalysis -- 1.3. Permutations of Enzyme Structure During Catalysis -- 1.4. Extension to Other Target Classes -- 1.5. Other Reasons for Studying Enzymes -- 1.6. Summary -- References -- 2. Enzyme Reaction Mechanisms -- Key Learning Points -- 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 Bound 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. Typical Values of Steady State Kinetic Parameters -- 2.6. Graphical Determination of kcat and KM -- 2.7. Reactions Involving Multiple Substrates -- 2.7.1. Bisubstrate Reaction Mechanisms -- 2.8. Summary -- References -- 3. Reversible Modes of Inhibitor Interactions with Enzymes -- Key Learning Points -- 3.1. Enzyme-Inhibitor Binding Equilibria -- 3.2. Competitive Inhibition -- 3.3. Noncompetitive Inhibition -- 3.3.1. Mutual Exclusivity Studies -- 3.3.2. Noncompetitive Inhibition by Active Site-Directed Inhibitors -- 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 Optimization -- 3.7. Enzyme Reactions on Macromolecular Substrates -- 3.7.1. Challenges in Inhibiting Protein-…
  table of contents: -- 9.2.1. Quiescent Affinity Labels -- 9.2.2. Potential Liabilities of Affinity Labels as Drugs -- 9.3. Mechanism-Based Inactivators -- 9.3.1. Distinguishing Features of Mechanism-Based Inactivation -- 9.3.2. Determination of the Partition Ratio -- 9.3.3. Potential Clinical Advantages of Mechanism-Based Inactivators -- 9.3.4. Examples of Mechanism-Based Inactivators as Drugs -- 9.4. Use of Affinity Labels as Mechanistic Tools -- 9.5. Summary -- References -- 10. Quantitative Biochemistry in the Pharmacological Evaluation of Drugs -- Key Learning Points -- 10.1. In Vitro ADMET Properties -- 10.1.1. Exponential Decay Processes and the Definition of Half-Life -- 10.1.2. Caco-2 Cell Permeability as a Surrogate for Intestinal Absorption -- 10.1.3. Whole Blood or Plasma Stability -- 10.1.4. Plasma Protein Binding -- 10.1.5. Metabolism of Xenobiotics in the Liver -- 10.1.6. Hepatocyte, S9, and Microsome Stability -- 10.1.7. CYP450 Mediated Metabolism -- 10.1.8. Cytochrome P450 Inhibition -- 10.1.9. hERG Inhibition -- 10.2. In Vivo Pharmacokinetic Studies -- 10.2.1. General Considerations and Curve Fitting Parameters -- 10.2.2. Kinetic Models of Drug PK -- 10.2.3. Absorption and Bioavailability -- 10.2.4. Factors Affecting PK Parameters.
  table of contents: Note continued: 10.2.5. Allometric Scaling of Drug Pharmacokinetics -- 10.3. Metabolite Identification -- 10.4. Measures of Target Occupancy -- 10.4.1. Radiometric Imaging -- 10.4.2. Ex Vivo Determination of Target Occupancy -- 10.4.3. Pharmacodynamic Measures of Target Engagement -- 10.5. Summary -- References -- APPENDIX 1 KINETICS OF BIOCHEMICAL REACTIONS -- A1.1. 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 -- 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 -- A5.1. Uncertainty Propagation for Addition or Subtraction of Two Experimental Parameters -- A5.2. Uncertainty Propagation for Multiplication or Division of Two Experimental Parameters -- A5.3. Uncertainty Propagation for Multiplication or Division of an Experimental Parameter by A Constant -- A5.4. Uncertainty Propagation for an Experimental Parameter Raised by an Exponent -- A5.5. Uncertainty Propagation for a General Function of Experimental Parameters -- Reference -- 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.
  note: by Robert A. Copeland.
  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 Enzym…
  note: Includes bibliographical references and index.
  subject:
    topic: Enzyme inhibitors
    topic: Therapeutic use
    topic: Testing
  subject:
    topic: Drugs
    topic: Design
  subject:
    topic: Enzyme inhibitors
    topic: Structure-activity relationships
  subject:
    topic: Enzyme Inhibitors
    topic: therapeutic use
  subject:
    topic: Drug Design
  subject:
    topic: Enzyme Inhibitors
    topic: chemistry
  classification: QP601.5 .C66 2013
  classification: 615/.19
  classification: QU 143
  related item:
    title info:
      title: Evaluation of enzyme inhibitors in drug discovery
    name:
      name part: Copeland, Robert Allen.
    origin info:
      publisher: Hoboken, N.J. : Wiley, ©2013
      edition: 2nd ed.
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  identifier: http://proxy.library.tamu.edu/login
  record info:
    record content source: DLC
    record creation date: 121114
    record change date: 20260214202149.8
    record identifier: in00004680314
    language of cataloging:
      language term: eng