1. Introduction 1.1. Overview 1.2. Drugs Discovered without Rational Design 1.2.1. Medicinal Chemistry Folklore 1.2.2. Discovery of Penicillins 1.2.3. Discovery of Librium 1.2.4. Discovery of Drugs through Metabolism Studies 1.2.5. Discovery of Drugs through Clinical Observations 1.3. Overview of Modern Rational Drug Design 1.3.1. Overview of Drug Targets 1.3.2. Identification and Validation of Targets for Drug Discovery 1.3.3. Alternatives to Target-Based Drug Discovery 1.3.4. Lead Discovery 1.3.5. Lead Modification (Lead Optimization) 1.3.5.1. Potency 1.3.5.2. Selectivity 1.3.5.3. Absorption, Distribution, Metabolism, and Excretion (ADME) 1.3.5.4. Intellectual Property Position 1.3.6. Drug Development 1.3.6.1. Preclinical Development 1.3.6.2. Clinical Development (Human Clinical Trials) 1.3.6.3. Regulatory Approval to Market the Drug 1.4. Epilogue 1.5. General References 1.6. Problems References 2. Lead Discovery and Lead Modification 2.1. Lead Discovery 2.1.1. General Considerations 2.1.2. Sources of Lead Compounds 2.1.2.1. Endogenous Ligands 2.1.2.2. Other Known Ligands 2.1.2.3. Screening of Compounds 2.1.2.3.1. Sources of Compounds for Screening 2.1.2.3.1.1. Natural Products 2.1.2.3.1.2. Medicinal Chemistry Collections and Other "Handcrafted" Compounds 2.1.2.3.1.3. High-Throughput Organic Synthesis 2.1.2.3.1.3.1. Solid-Phase Library Synthesis 2.1.2.3.1.3.2. Solution-Phase Library Synthesis 2.1.2.3.1.3.3. Evolution of HTOS 2.1.2.3.2. Drug-Like, Lead-Like, and Other Desirable Properties of Compounds for Screening 2.1.2.3.3. Random Screening 2.1.2.3.4. Targeted (or Focused) Screening, Virtual Screening, and Computational Methods in Lead Discovery 2.1.2.3.4.1. Virtual Screening Database 2.1.2.3.4.2. Virtual Screening Hypothesis 2.1.2.3.5. Hit-To-Lead Process 2.1.2.3.6. Fragment-based Lead Discovery 2.2. Lead Modification 2.2.1. Identification of the Active Part: The Pharmacophore 2.2.2. Functional Group Modification 2.2.3. Structure¿Activity Relationships 2.2.4. Structure Modifications to Increase Potency, Therapeutic Index, and ADME Properties 2.2.4.1. Homologation 2.2.4.2. Chain Branching 2.2.4.3. Bioisosterism 2.2.4.4. Conformational Constraints and Ring-Chain Transformations 2.2.4.5. Peptidomimetics 2.2.5. Structure Modifications to Increase Oral Bioavailability and Membrane Permeability 2.2.5.1. Electronic Effects: The Hammett Equation 2.2.5.2. Lipophilicity Effects 2.2.5.2.1. Importance of Lipophilicity 2.2.5.2.2. Measurement of Lipophilicities 2.2.5.2.3. Computer Automation of log P Determination 2.2.5.2.4. Membrane Lipophilicity 2.2.5.3. Balancing Potency of Ionizable Compounds with Lipophilicity and Oral Bioavailability 2.2.5.4. Properties that Influence Ability to Cross the Blood¿Brain Barrier 2.2.5.5. Correlation of Lipophilicity with Promiscuity and Toxicity 2.2.6. Computational Methods in Lead Modification 2.2.6.1. Overview 2.2.6.2. Quantitative Structure¿Activity Relationships (QSARs) 2.2.6.2.1. Historical Overview. Steric Effects: The Taft Equation and Other Equations 2.2.6.2.2. Methods Used to Correlate Physicochemical Parameters with Biological Activity 2.2.6.2.2.1. Hansch Analysis: A Linear Multiple Regression Analysis 2.2.6.2.2.2. Manual Stepwise Methods: Topliss Operational Schemes and Others 2.2.6.2.2.3. Batch Selection Methods: Batchwise Topliss Operational Scheme, Cluster Analysis, and Others 2.2.6.2.2.4. Free and Wilson or de Novo Method 2.2.6.2.2.5. Computational Methods for ADME Descriptors 2.2.6.3. Scaffold Hopping 2.2.6.4. Molecular Graphics-Based Lead Modification 2.2.7. Epilogue 2.3. General References 2.4. Problems References 3. Receptors 3.1. Introduction 3.2. Drug¿Receptor Interactions 3.2.1. General Considerations 3.2.2. Important Interactions (Forces) Involved in the Drug¿Receptor Complex 3.2.2.1. Covalent Bonds 3.2.2.2. Ionic (or Electrostatic) Interactions 3.2.2.3. Ion¿Dipole and Dipole¿Dipole Interactions 3.2.2.4. Hydrogen Bonds 3.2.2.5. Charge¿Transfer Complexes 3.2.2.6. Hydrophobic Interactions 3.2.2.7. Cation¿p Interaction 3.2.2.8. Halogen Bonding 3.2.2.9. van der Waals or London Dispersion Forces 3.2.2.10. Conclusion 3.2.3. Determination of Drug¿Receptor Interactions 3.2.4. Theories for Drug¿Receptor Interactions 3.2.4.1. Occupancy Theory 3.2.4.2. Rate Theory 3.2.4.3. Induced-Fit Theory 3.2.4.4. Macromolecular Perturbation Theory 3.2.4.5. Activation¿Aggregation Theory 3.2.4.6. The Two-State (Multistate) Model of Receptor Activation 3.2.5. Topographical and Stereochemical Considerations 3.2.5.1. Spatial Arrangement of Atoms 3.2.5.2. Drug and Receptor Chirality 3.2.5.3. Diastereomers 3.2.5.4. Conformational Isomers 3.2.5.5. Atropisomers 3.2.5.6. Ring Topology 3.2.6. Case History of the Pharmacodynamically Driven Design of a Receptor Antagonist: Cimetidine 3.2.7. Case History of the Pharmacokinetically Driven Design of Suvorexant 3.3. General References 3.4. Problems References 4. Enzymes 4.1. Enzymes as Catalysts 4.1.1. What are Enzymes? 4.1.2. How do Enzymes Work? 4.1.2.1. Specificity of Enzyme-Catalyzed Reactions 4.1.2.1.1. Binding Specificity 4.1.2.1.2. Reaction Specificity 4.1.2.2. Rate Acceleration 4.2. Mechanisms of Enzyme Catalysis 4.2.1. Approximation 4.2.2. Covalent Catalysis 4.2.3. General Acid¿Base Catalysis 4.2.4. Electrostatic Catalysis 4.2.5. Desolvation 4.2.6. Strain or Distortion 4.2.7. Example of the Mechanisms of Enzyme Catalysis 4.3. Coenzyme Catalysis 4.3.1. Pyridoxal 5'-Phosphate 4.3.1.1. Racemases 4.3.1.2. Decarboxylases 4.3.1.3. Aminotransferases (Formerly Transaminases) 4.3.1.4. PLP-Dependent ß-Elimination 4.3.2. Tetrahydrofolate and Pyridine Nucleotides 4.3.3. Flavin 4.3.3.1. Two-Electron (Carbanion) Mechanism 4.3.3.2. Carbanion Followed by Two One-Electron Transfers 4.3.3.3. One-Electron Mechanism 4.3.3.4. Hydride Mechanism 4.3.4. Heme 4.3.5. Adenosine Triphosphate and Coenzyme A 4.4. Enzyme Catalysis in Drug Discovery 4.4.1. Enzymatic Synthesis of Chiral Drug Intermediates 4.4.2. Enzyme Therapy 4.5. General References 4.6. Problems References 5. Enzyme Inhibition and Inactivation 5.1. Why Inhibit an Enzyme? 5.2. Reversible Enzyme Inhibitors 5.2.1. Mechanism of Reversible Inhibition 5.2.2. Selected Examples of Competitive Reversible Inhibitor Drugs 5.2.2.1. Simple Competitive Inhibition 5.2.2.1.1. Epidermal Growth Factor Receptor Tyrosine Kinase as a Target for Cancer 5.2.2.1.2. Discovery and Optimization of EGFR Inhibitors 5.2.2.2. Stabilization of an Inactive Conformation: Imatinib, an Antileukemia Drug 5.2.2.2.1. The Target: Bcr-Abl, a Constitutively Active Kinase 5.2.2.2.2. Lead Discovery and Modification 5.2.2.2.3. Binding Mode of Imatinib to Abl Kinase 5.2.2.2.4. Inhibition of Other Kinases by Imatinib 5.2.2.3. Alternative Substrate Inhibition: Sulfonamide Antibacterial Agents (Sulfa Drugs) 5.2.2.3.1. Lead Discovery 5.2.2.3.2. Lead Modification 5.2.2.3.3. Mechanism of Action 5.2.3. Transition State Analogs and Multisubstrate Analogs 5.2.3.1. Theoretical Basis 5.2.3.2. Transition State Analogs 5.2.3.2.1. Enalaprilat 5.2.3.2.2. Pentostatin 5.2.3.2.3. Forodesine and DADMe-ImmH 5.2.3.2.4. Multisubstrate Analogs 5.2.4. Slow, T ight-Binding Inhibitors 5.2.4.1. Theoretical Basis 5.2.4.2. Captopril, Enalapril, Lisinopril, and Other Antihypertensive Drugs 5.2.4.2.1. Humoral Mechanism for Hypertension 5.2.4.2.2. Lead Discovery 5.2.4.2.3. Lead Modification and Mechanism of Action 5.2.4.2.4. Dual-Acting Drugs: Dual-Acting Enzyme Inhibitors 5.2.4.3. Lovastatin (Mevinolin) and Simvastatin, Antihypercholesterolemic Drugs 5.2.4.3.1. Cholesterol and Its Effects 5.2.4.3.2. Lead Discovery 5.2.4.3.3. Mechanism of Action 5.2.4.3.4. Lead Modification 5.2.4.4. Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor and Antidiabetes Drug 5.2.5. Case History of Rational Drug Design of an Enzyme Inhibitor: Ritonavir 5.2.5.1. Lead Discovery 5.2.5.2. Lead Modification 5.3. Irreversible Enzyme Inhibitors 5.3.1. Potential of Irreversible Inhibition 5.3.2. Affinity Labeling Agents 5.3.2.1. Mechanism of Action 5.3.2.2. Selected Affinity Labeling Agents 5.3.2.2.1. Penicillins and Cephalosporins/Cephamycins 5.3.2.2.2. Aspirin 5.3.3. Mechanism-Based Enzyme Inactivators 5.3.3.1. Theoretical...