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Evaluation of enzyme inhibitors in drug discovery : a guide for medicinal chemists and pharmacologists /
"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 com...
| Clasificación: | Libro Electrónico |
|---|---|
| Autor principal: | |
| Formato: | Electrónico eBook |
| Idioma: | Inglés |
| Publicado: |
Hoboken, N.J. :
Wiley,
©2013.
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| Edición: | 2nd ed. |
| Temas: | |
| Acceso en línea: | Texto completo |
MARC
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| 100 | 1 | |a Copeland, Robert Allen. | |
| 245 | 1 | 0 | |a Evaluation of enzyme inhibitors in drug discovery : |b a guide for medicinal chemists and pharmacologists / |c by Robert A. Copeland. |
| 250 | |a 2nd ed. | ||
| 260 | |a Hoboken, N.J. : |b Wiley, |c ©2013. | ||
| 300 | |a 1 online resource | ||
| 336 | |a text |b txt |2 rdacontent | ||
| 337 | |a computer |b c |2 rdamedia | ||
| 338 | |a online resource |b cr |2 rdacarrier | ||
| 504 | |a Includes bibliographical references and index. | ||
| 500 | |a 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* <<Ki: Aspartyl Protease Inhibitors. 6.6.5 Example of Scheme C When k6 Is Very Small: Selective COX2 Inhibitors. 6.7 Summary. References. 7. Tight Binding Inhibitors. 7.1 Effects of Tight Binding Inhibition Concentration-Response Data. 7.2 The IC50 Value Depends on Kiapp and [E]T.7.3 Morrison's Quadratic Equation for Fiting Concentration-Response Data for Tight Binding Inhibitors. 7.3.1 Optimizing Conditions for Kiapp Determination Using Morrison's Equation. 7.3.2 Limits on Kiapp Determinations. 7.3.3 Use of a Cubic Equation When Both Substrate and Inhibitor Are Tight Binding. 7.4 Determining Modality for Tight Binding Enzyme Inhibitors. 7.5 Tight Binding Inhibitors Often Display Slow Binding Behavior. 7.6 Practical Approaches to Overcoming the Tight Binding Limit in Determine Ki. 7.7 Enzyme-Reaction Intermediate Analogues as Example of Tight Binding Inhibitors. 7.7.1 Bisubstrate Analogues. 7.7.2 Testing for Transition State Mimicry. 7.8 Potential Clinical Advantages of Tight Binding Inhibitors. 7.9 Determination of [E]T Using Tight Binding Inhibitors. 7.10 Summary. References. 8. Irreversible Enzyme Inactivators. 8.1 Kinetic Evaluation of Irreversible Enzyme Inactivators. 8.2 Affinity Labels. 8.2.1 Quiescent Affinity Labels. 8.2.2 Potential Liabilities of Affinity Labels as Drugs. 8.3 Mechanism-Based Inactivators. 8.3.1 Distinguishing Features of Mechanism-Based Inactivation. 8.3.2 Determination of the Partition Ratio. 8.3.3 Potential Clinical Advantages of Mechanism-Based Inactivators. 8.3.4 Examples of Mechanism-Based Inactivators as Drugs. 8.4 Use of Affinity Labels as Mechanistic Tools. 8.5 Summary. References. 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. | ||
| 520 | |a "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. | ||
| 588 | 0 | |a Print version record and CIP data provided by publisher. | |
| 505 | 0 | 0 | |g Machine generated contents note: |g 1. |t Why Enzymes As Drug Targets? -- |t Key Learning Points -- |g 1.1. |t Enzymes Are Essential for Life -- |g 1.2. |t Enzyme Structure and Catalysis -- |g 1.3. |t Permutations of Enzyme Structure During Catalysis -- |g 1.4. |t Extension to Other Target Classes -- |g 1.5. |t Other Reasons for Studying Enzymes -- |g 1.6. |t Summary -- |t References -- |g 2. |t Enzyme Reaction Mechanisms -- |t Key Learning Points -- |g 2.1. |t Initial Binding of Substrate -- |g 2.2. |t Noncovalent Forces in Reversible Ligand Binding to Enzymes -- |g 2.2.1. |t Electrostatic Forces -- |g 2.2.2. |t Hydrogen Bonds -- |g 2.2.3. |t Hydrophobic Forces -- |g 2.2.4. |t Van der Waals Forces -- |g 2.3. |t Transformations of the Bound Substrate -- |g 2.3.1. |t Strategies for Transition State Stabilization -- |g 2.3.2. |t Enzyme Active Sites Are Most Complementary to the Transition State Structure -- |g 2.4. |t Steady State Analysis of Enzyme Kinetics -- |g 2.4.1. |t Factors Affecting the Steady State Kinetic Constants -- |g 2.5. |t Typical Values of Steady State Kinetic Parameters -- |g 2.6. |t Graphical Determination of kcat and KM -- |g 2.7. |t Reactions Involving Multiple Substrates -- |g 2.7.1. |t Bisubstrate Reaction Mechanisms -- |g 2.8. |t Summary -- |t References -- |g 3. |t Reversible Modes of Inhibitor Interactions with Enzymes -- |t Key Learning Points -- |g 3.1. |t Enzyme-Inhibitor Binding Equilibria -- |g 3.2. |t Competitive Inhibition -- |g 3.3. |t Noncompetitive Inhibition -- |g 3.3.1. |t Mutual Exclusivity Studies -- |g 3.3.2. |t Noncompetitive Inhibition by Active Site-Directed Inhibitors -- |g 3.4. |t Uncompetitive Inhibition -- |g 3.5. |t Inhibition Modality in Bisubstrate Reactions -- |g 3.6. |t Value of Knowing Inhibitor Modality -- |g 3.6.1. |t Quantitative Comparisons of Inhibitor Affinity -- |g 3.6.2. |t Relating Ki to Binding Energy -- |g 3.6.3. |t Defining Target Selectivity by Ki Values -- |g 3.6.4. |t Potential Advantages and Disadvantages of Different Inhibition Modalities in Vivo -- |g 3.6.5. |t Knowing Inhibition Modality Is Important for Structure-Based Lead Optimization -- |g 3.7. |t Enzyme Reactions on Macromolecular Substrates -- |g 3.7.1. |t Challenges in Inhibiting Protein-Protein Interactions -- |g 3.7.2. |t Hot Spots in Protein-Protein Interactions -- |g 3.7.3. |t Factors Affecting Protein-Protein Interactions -- |g 3.7.4. |t Separation of Binding and Catalytic Recognition Elements -- |g 3.7.5. |t Noncompetitive Inhibition by Active Site-Binding Molecules for Exosite Utilizing Enzymes -- |g 3.7.6. |t Processive and Distributive Mechanisms of Catalysis -- |g 3.7.7. |t Effect of Substrate Conformation on Enzyme Kinetics -- |g 3.7.8. |t Inhibitor Binding to Substrates -- |g 3.8. |t Summary -- |t References -- |g 4. |t Assay Considerations for Compound Library Screening -- |t Key Learning Points -- |g 4.1. |t Measures of Assay Performance -- |g 4.1.1. |t Calibration Curves -- |g 4.1.2. |t Total, Background, and Specific Signal -- |g 4.1.3. |t Defining Inhibition, Signal Robustness, and Hit Criteria -- |g 4.2. |t Measuring Initial Velocity -- |g 4.2.1. |t End-Point and Kinetic Readouts -- |g 4.2.2. |t Effect of Enzyme Concentration -- |g 4.2.3. |t Other Factors Affecting Initial Velocity -- |g 4.3. |t Balanced Assay Conditions -- |g 4.3.1. |t Balancing Conditions for Multisubstrate Reactions -- |g 4.4. |t Order of Reagent Addition -- |g 4.5. |t Use of Natural Substrates and Enzymes -- |g 4.6. |t Coupled Enzyme Assays -- |g 4.7. |t Hit Validation -- |g 4.7.1. |t Determination of Hit Reproducibility -- |g 4.7.2. |t Verification of Chemical Purity and Structure -- |g 4.7.3. |t Hit Verification in Orthogonal Assays -- |g 4.7.4. |t Chemical and Pharmacological Tractability -- |g 4.7.5. |t Promiscuous Inhibitors -- |g 4.7.6. |t Prioritization of Confirmed Hits -- |g 4.7.7. |t Hit Expansion -- |g 4.8. |t Summary -- |t References -- |g 5. |t Lead Optimization and Structure-Activity Relationships for Reversible Inhibitors -- |t Key Learning Points -- |g 5.1. |t Concentration-Response Plots and IC50 Determination -- |g 5.1.1. |t Hill Coefficient -- |g 5.1.2. |t Graphing and Reporting Concentration-Response Data -- |g 5.2. |t Testing for Reversibility -- |g 5.3. |t Determining Reversible Inhibition Modality and Dissociation Constant -- |g 5.4. |t Comparing Relative Affinity -- |g 5.4.1. |t Compound Selectivity -- |g 5.5. |t Associating Cellular Effects with Target Enzyme Inhibition -- |g 5.5.1. |t Cellular Phenotype Should Be Consistent with Genetic Knockout or Knockdown of the Target Enzyme -- |g 5.5.2. |t Cellular Activity Should Require a Certain Affinity for the Target Enzyme -- |g 5.5.3. |t Buildup of Substrate and/or Diminution of Product for the Target Enzyme Should Be Observed in Cells -- |g 5.5.4. |t Cellular Phenotype Should Be Reversed by Cell-Permeable Product or Downstream Metabolites of the Target Enzyme Activity -- |g 5.5.5. |t Mutation of the Target Enzyme Should Lead to Resistance or Hypersensitivity to Inhibitors -- |g 5.6. |t Summary -- |t References -- |g 6. |t Slow Binding Inhibitors -- |t Key Learning Points -- |g 6.1. |t Determining kobs: The Rate Constant for Onset of Inhibition -- |g 6.2. |t Mechanisms of Slow Binding Inhibition -- |g 6.3. |t Determination of Mechanism and Assessment of True Affinity -- |g 6.3.1. |t Potential Clincial Advantages of Slow Off-Rate Inhibitors -- |g 6.4. |t Determining Inhibition Modality for Slow Binding Inhibitors -- |g 6.5. |t SAR for Slow Binding Inhibitors -- |g 6.6. |t Some Examples of Pharmacologically Interesting Slow Binding Inhibitors -- |g 6.6.1. |t Examples of Scheme B: Inhibitors of Zinc Peptidases and Proteases -- |g 6.6.2. |t Example of Scheme C: Inhibition of Dihydrofolate Reductase by Methotrexate -- |g 6.6.3. |t Example of Scheme C: Inhibition of Calcineurin by FKBP-Inhibitor Complexes -- |g 6.6.4. |t Example of Scheme C When Ki <<Ki: Aspartyl Protease Inhibitors -- |g 6.6.5. |t Example of Scheme C When k6 Is Very Small: Selective COX2 Inhibitors -- |g 6.7. |t Summary -- |t References -- |g 7. |t Tight Binding Inhibition -- |t Key Learning Points -- |g 7.1. |t Effects of Tight Binding Inhibition on Concentration-Response Data -- |g 7.2. |t IC50 Value Depends on Kiapp and [E]T -- |g 7.3. |t Morrison's Quadratic Equation for Fitting Concentration-Response Data for Tight Binding Inhibitors -- |g 7.3.1. |t Optimizing Conditions for Kiapp Determination Using Morrison's Equation -- |g 7.3.2. |t Limits on Kiapp Determinations -- |g 7.3.3. |t Use of a Cubic Equation When Both Substrate and Inhibitor Are Tight Binding -- |g 7.4. |t Determining Modality for Tight Binding Enzyme Inhibitors -- |g 7.5. |t Tight Binding Inhibitors Often Display Slow Binding Behavior -- |g 7.6. |t Practical Approaches to Overcoming the Tight Binding Limit in Determining Ki -- |g 7.7. |t Enzyme-Reaction Intermediate Analogues as Examples of Tight Binding Inhibitors -- |g 7.7.1. |t Bisubstrate Analogues -- |g 7.7.2. |t Testing for Transition State Mimicry -- |g 7.8. |t Potential Clinical Advantages of Tight Binding Inhibitors -- |g 7.9. |t Determination of [E]T Using Tight Binding Inhibitors -- |g 7.10. |t Summary -- |t References -- |g 8. |t Drug-Target Residence Time -- |t Key Learning Points -- |g 8.1. |t Open and Closed Systems in Biology -- |g 8.2. |t Static View of Drug-Target Interactions -- |g 8.3. |t Conformational Adaptation in Drug-Target Interactions -- |g 8.3.1. |t Conformational Selection Model -- |g 8.3.2. |t Induced-Fit Model -- |g 8.3.3. |t Kinetic Distinction Between Conformational Selection and Induced-Fit Mechanisms -- |g 8.4. |t Impact of Residence Time on Natural Receptor-Ligand Function -- |g 8.4.1. |t Immune Response -- |g 8.4.2. |t Control of Protease Activity by Natural Inhibitors -- |g 8.5. |t Impact of Drug-Target Residence Time on Drug Action -- |g 8.5.1. |t Mathematical Definition of Residence Time for Different Mechanisms of Drug-Target Interaction -- |g 8.5.2. |t Impact of Residence Time on Cellular Activity -- |g 8.5.3. |t Impact on Efficacy and Duration in Vivo -- |g 8.5.4. |t Temporal Target Selectivity and Drug Safety -- |g 8.6. |t Experimental Measures of Drug-Target Residence Time -- |g 8.6.1. |t Kinetic Analysis of Approach to Equilibrium -- |g 8.6.2. |t Jump-Dilution Experiments -- |g 8.6.3. |t Separation Methods -- |g 8.6.4. |t Spectroscopic Differentiation -- |g 8.6.5. |t Immobilized Binding Partner Methods -- |g 8.7. |t Drug-Target Residence Time Structure-Activity Relationships -- |g 8.7.1. |t Structural Changes Associated with Conformational Adaptation -- |g 8.7.2. |t Thermodynamics of Drug-Target Complex Dissociation -- |g 8.7.3. |t Retrograded Induced-Fit Model of Drug-Target Complex Dissociation -- |g 8.8. |t Recent Applications of the Residence Time Concept -- |g 8.9. |t Limitations of Drug-Target Residence Time -- |g 8.10. |t Summary -- |t References -- |g 9. |t Irreversible Enzyme Inactivators -- |t Key Learning Points -- |g 9.1. |t Kinetic Evaluation of Irreversible Enzyme Inactivators -- |g 9.2. |t Affinity Labels |
| 505 | 0 | 0 | |g -- |g 9.2.1. |t Quiescent Affinity Labels -- |g 9.2.2. |t Potential Liabilities of Affinity Labels as Drugs -- |g 9.3. |t Mechanism-Based Inactivators -- |g 9.3.1. |t Distinguishing Features of Mechanism-Based Inactivation -- |g 9.3.2. |t Determination of the Partition Ratio -- |g 9.3.3. |t Potential Clinical Advantages of Mechanism-Based Inactivators -- |g 9.3.4. |t Examples of Mechanism-Based Inactivators as Drugs -- |g 9.4. |t Use of Affinity Labels as Mechanistic Tools -- |g 9.5. |t Summary -- |t References -- |g 10. |t Quantitative Biochemistry in the Pharmacological Evaluation of Drugs -- |t Key Learning Points -- |g 10.1. |t In Vitro ADMET Properties -- |g 10.1.1. |t Exponential Decay Processes and the Definition of Half-Life -- |g 10.1.2. |t Caco-2 Cell Permeability as a Surrogate for Intestinal Absorption -- |g 10.1.3. |t Whole Blood or Plasma Stability -- |g 10.1.4. |t Plasma Protein Binding -- |g 10.1.5. |t Metabolism of Xenobiotics in the Liver -- |g 10.1.6. |t Hepatocyte, S9, and Microsome Stability -- |g 10.1.7. |t CYP450 Mediated Metabolism -- |g 10.1.8. |t Cytochrome P450 Inhibition -- |g 10.1.9. |t hERG Inhibition -- |g 10.2. |t In Vivo Pharmacokinetic Studies -- |g 10.2.1. |t General Considerations and Curve Fitting Parameters -- |g 10.2.2. |t Kinetic Models of Drug PK -- |g 10.2.3. |t Absorption and Bioavailability -- |g 10.2.4. |t Factors Affecting PK Parameters. |
| 505 | 0 | 0 | |g Note continued: |g 10.2.5. |t Allometric Scaling of Drug Pharmacokinetics -- |g 10.3. |t Metabolite Identification -- |g 10.4. |t Measures of Target Occupancy -- |g 10.4.1. |t Radiometric Imaging -- |g 10.4.2. |t Ex Vivo Determination of Target Occupancy -- |g 10.4.3. |t Pharmacodynamic Measures of Target Engagement -- |g 10.5. |t Summary -- |t References -- |g APPENDIX 1 |t KINETICS OF BIOCHEMICAL REACTIONS -- |g A1.1. |t Law of Mass Action and Reaction Order -- |g A1.2. |t First-Order Reaction Kinetics -- |g A1.3. |t Second-Order Reaction Kinetics -- |g A1.4. |t Pseudo-First-Order Reaction Conditions -- |g A1.5. |t Approach to Equilibrium: An Example of the Kinetics of Reversible Reactions -- |g APPENDIX 2 |t DERIVATION OF THE ENZYME-LIGAND BINDING ISOTHERM EQUATION -- |g APPENDIX 3 |t SERIAL DILUTION SCHEMES -- |g APPENDIX 4 |t RELATIONSHIP BETWEEN [I]/IC50 AND PERCENTAGE INHIBITION OF ENZYME ACTIVITY WHEN H = 1 -- |g APPENDIX 5 |t PROPAGATION OF UNCERTAINTIES IN EXPERIMENTAL MEASUREMENTS -- |g A5.1. |t Uncertainty Propagation for Addition or Subtraction of Two Experimental Parameters -- |g A5.2. |t Uncertainty Propagation for Multiplication or Division of Two Experimental Parameters -- |g A5.3. |t Uncertainty Propagation for Multiplication or Division of an Experimental Parameter by A Constant -- |g A5.4. |t Uncertainty Propagation for an Experimental Parameter Raised by an Exponent -- |g A5.5. |t Uncertainty Propagation for a General Function of Experimental Parameters -- |t Reference -- |g APPENDIX 6 |t USEFUL PHYSICAL CONSTANTS AT DIFFERENT TEMPERATURES -- |g APPENDIX 7 |t COMMON RADIOACTIVE ISOTOPES USED IN STUDIES OF ENZYMES -- |g APPENDIX 8 |t COMMON PREFIXES FOR UNITS IN BIOCHEMISTRY -- |g APPENDIX 9 |t SOME AROMATIC RING SYSTEMS COMMONLY FOUND IN DRUGS -- |g APPENDIX 10 |t RESIDUAL PLOTS. |
| 590 | |a ProQuest Ebook Central |b Ebook Central Academic Complete | ||
| 650 | 0 | |a Enzyme inhibitors |x Therapeutic use |x Testing. | |
| 650 | 0 | |a Drugs |x Design. | |
| 650 | 0 | |a Enzyme inhibitors |x Structure-activity relationships. | |
| 650 | 1 | 2 | |a Enzyme Inhibitors |x therapeutic use |
| 650 | 2 | 2 | |a Drug Design |
| 650 | 2 | 2 | |a Enzyme Inhibitors |x chemistry |
| 650 | 6 | |a Antienzymes |x Emploi en thérapeutique |x Essais. | |
| 650 | 6 | |a Médicaments |x Conception. | |
| 650 | 6 | |a Antienzymes |x Relations structure-activité. | |
| 650 | 7 | |a MEDICAL |x Drug Guides. |2 bisacsh | |
| 650 | 7 | |a MEDICAL |x Nursing |x Pharmacology. |2 bisacsh | |
| 650 | 7 | |a MEDICAL |x Pharmacology. |2 bisacsh | |
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| 758 | |i has work: |a Evaluation of Enzyme Inhibitors in Drug Discovery (Text) |1 https://id.oclc.org/worldcat/entity/E39PCGcqvrFJcgCBmBMCcRmB8y |4 https://id.oclc.org/worldcat/ontology/hasWork | ||
| 776 | 0 | 8 | |i Print version: |a Copeland, Robert Allen. |t Evaluation of enzyme inhibitors in drug discovery. |b 2nd ed. |d Hoboken, N.J. : Wiley, ©2013 |z 9781118488133 |w (DLC) 2012045179 |
| 856 | 4 | 0 | |u https://ebookcentral.uam.elogim.com/lib/uam-ebooks/detail.action?docID=1120975 |z Texto completo |
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