Description
Pharmacology in Drug Discovery and Development: Understanding Drug Response, Second Edition, is an introductory resource illustrating how pharmacology can be used to furnish the tools necessary to analyze different drug behavior and trace this behavior to its root cause or molecular mechanism of action. The concepts discussed in this book allow for the application of more predictive pharmacological procedures aimed at increasing therapeutic efficacy that will lead to more successful drug development.
Chapters logically build upon one another to show how to characterize the pharmacology of any given molecule and allow for more informed predictions of drug effects in all biological systems. New chapters are dedicated to the interdisciplinary drug discovery environment in both industry and academia, and special techniques involved in new drug screening and lead optimization.
This edition has been fully revised to address the latest advances and research related to real time kinetic assays, pluridimensional efficacy, signaling bias, irreversible and chemical antagonism, allosterically-induced bias, pharmacokinetics and safety, target and pathway validation, and much more. With numerous valuable chapter summaries, detailed references, practical examples and case studies throughout, Dr. Kenakin successfully navigates a highly complex subject, making it accessible for students, professors, and new researchers working in pharmacology and drug discovery.
Chapter
Linking Observed Pharmacology With Molecular Mechanism
Descriptive Pharmacology: I
2 Drug Affinity and Efficacy
Drugs With Multiple Efficacies
Quantifying Agonist Activity
Descriptive Pharmacology: II
3 Predicting Agonist Effect
Agonist Response in Different Tissues
The Black–Leff Operational Model of Agonism
Applying the Black–Leff Model to Predict Agonism
Descriptive Pharmacology: III
4 Drug Antagonism: Orthosteric Drug Effects
Mechanism(s) of Receptor Antagonism
Orthosteric (Competitive and Noncompetitive) Antagonism
Slow Dissociation Kinetics and Noncompetitive Antagonism
Partial and Inverse Agonists
Antagonist Effects In Vivo
Antagonists With Multiple Activities
Descriptive Pharmacology: IV
5 Allosteric Drug Effects
Unique Effects of Allosteric Modulators
The Potential to Alter the Interaction of Very Large Proteins
The Potential to Modulate but not Completely Activate and/or Inhibit Receptor Function
Preservation of Physiological Patterns
Reduction in Side-Effects
Can Produce Texture in Antagonism
Can Have Separate Effects on Agonist Affinity and Efficacy
Allosteric Modulators Exercise “Probe Dependence”
Quantifying Allosteric Effect
Descriptive Pharmacology: V
6 Enzymes as Drug Targets
Enzyme Inhibition to Alter Levels of Normal Physiological Cellular Molecules
Blockade of Enzyme Activity That Becomes Pathophysiological
Blockade of an Enzyme That Exclusively Takes Part in a Pathophysiological Process
Blockade of Hyperactivity From Enzymes
Reversible Enzyme Inhibition
Noncompetitive Inhibition
Irreversible Enzyme Inhibition
Allosteric Enzyme Modulation
Intracellular Effects of Enzyme-Active Drugs
7 Pharmacokinetics I: Permeation and Metabolism
The Importance of Drug Concentration
“Drug-Like” Properties of Molecules
8 Pharmacokinetics II: Distribution and Multiple Dosing
Drugs in Motion: In Vivo Pharmacokinetics
The Central Compartment and In vivo Clearance
Nonlinear Pharmacokinetics
Scaling Data to Predict Human Pharmacokinetic Behavior
The “Dose” in Dose–Response
What Constitutes Drug Response?
The Importance of Kinetics In Vivo
Interaction With Receptors Mediating Autonomic Function
Blockade of hERG Potassium Channels
11 Pharmacology in Drug Discovery
Unique Aspects of Pharmacology in the Discovery Process
Target-Versus System-Based Discovery Strategies
Progression Scheme for Drug Discovery
Libraries and Molecules as Drug Sources
Pharmacological Assay Design
High-Throughput Screening
Appendix A: Answers to Chapter Questions
Appendix B: Derivations and Proofs
Successive Saturable Functions Leads to Amplification of Signals
The Potency of a Full Agonist Depends on Both Affinity and Efficacy
Derivation of the Black–Leff Operational Model
Derivation of Variable Slope Black–Leff Operational Model
Derivation of the Gaddum Equation for Competitive Antagonism
Correction of IC50 to pKB for Competitive Antagonists
Derivation of the Equation for Noncompetitive Antagonism
Derivation of the Equation for Allosteric Modulation
Derivation of the Equation for Allosteric Modulation with Direct Agonism
Derivation of the Michaelis–Menten Equation for Enzymes
Pharmacology in Drug Discovery and Development
：Understanding Drug Response
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