Preface xiii 1 From Traditional Medicine to Modern Drugs: Historical Perspective of Structure-Based Drug Design 1 1.1 Introduction 1 1.2 Drug Discovery During 1928-1980 1 1.3 The Beginning of Structure-Based Drug Design 6 1.4 Conclusions 12 References 13 Part One Concepts, Tools, Ligands, and Scaffolds for Structure-Based Design of Inhibitors 19 2 Design of Inhibitors of Aspartic Acid Proteases 21 2.1 Introduction 21 2.2 Design of Peptidomimetic Inhibitors of Aspartic Acid Proteases 22 2.3 Design of Statine-Based Inhibitors 24 2.

4 Design of Hydroxyethylene Isostere-Based Inhibitors 29 2.5 Design of Inhibitors with Hydroxyethylamine Isosteres 35 2.5.1 Synthesis of Optically Active α-Aminoalkyl Epoxide 37 2.6 Design of (Hydroxyethyl)urea-Based Inhibitors 40 2.7 (Hydroxyethyl)sulfonamide-Based Inhibitors 42 2.8 Design of Heterocyclic/Nonpeptidomimetic Aspartic Acid Protease Inhibitors 42 2.8.

1 Hydroxycoumarin- and Hydroxypyrone-Based Inhibitors 44 2.8.2 Design of Substituted Piperidine-Based Inhibitors 46 2.8.3 Design of Diaminopyrimidine-Based Inhibitors 50 2.8.4 Design of Acyl Guanidine-Based Inhibitors 51 2.8.

5 Design of Aminopyridine-Based Inhibitors 53 2.8.6 Design of Aminoimidazole- and Aminohydantoin-Based Inhibitors 53 2.9 Conclusions 56 References 56 3 Design of Serine Protease Inhibitors 67 3.1 Introduction 67 3.2 Catalytic Mechanism of Serine Protease 67 3.3 Types of Serine Protease Inhibitors 67 3.4 Halomethyl Ketone-Based Inhibitors 69 3.

5 Diphenyl Phosphonate-Based Inhibitors 70 3.6 Trifluoromethyl Ketone Based Inhibitors 73 3.6.1 Synthesis of Trifluoromethyl Ketones 76 3.7 Peptidyl Boronic Acid-Based Inhibitors 78 3.7.1 Synthesis of α-Aminoalkyl Boronic Acid Derivatives 83 3.8 Peptidyl α-Ketoamide- and α-Ketoheterocycle-Based Inhibitors 85 3.

8.1 Synthesis of α-Ketoamide and α-Ketoheterocyclic Templates 90 3.9 Design of Serine Protease Inhibitors Based Upon Heterocycles 93 3.9.1 Isocoumarin-Derived Irreversible Inhibitors 94 3.9.2 β-Lactam-Derived Irreversible Inhibitors 95 3.10 Reversible/Noncovalent Inhibitors 97 3.

11 Conclusions 104 References 105 4 Design of Proteasome Inhibitors 113 4.1 Introduction 113 4.2 Catalytic Mechanism of 20S Proteasome 113 4.3 Proteasome Inhibitors 114 4.3.1 Development of Boronate Proteasome Inhibitors 115 4.3.2 Development of β-Lactone Natural Product-Based Proteasome Inhibitors 116 4.

3.3 Development of Epoxy Ketone-Derived Inhibitors 118 4.3.4 Noncovalent Proteasome Inhibitors 120 4.4 Synthesis of β-Lactone Scaffold 121 4.5 Synthesis of Epoxy Ketone Scaffold 123 4.6 Conclusions 126 References 126 5 Design of Cysteine Protease Inhibitors 131 5.1 Introduction 131 5.

2 Development of Cysteine Protease Inhibitors with Michael Acceptors 132 5.3 Design of Noncovalent Cysteine Protease Inhibitors 136 5.4 Conclusions 140 References 140 6 Design of Metalloprotease Inhibitors 143 6.1 Introduction 143 6.2 Design of Matrix Metalloprotease Inhibitors 144 6.3 Design of Inhibitors of Tumor Necrosis Factor-α-Converting Enzymes 150 6.4 Conclusions 152 References 152 7 Structure-Based Design of Protein Kinase Inhibitors 155 7.1 Introduction 155 7.

2 Active Site of Protein Kinases 155 7.3 Catalytic Mechanism of Protein Kinases 156 7.4 Design Strategy for Protein Kinase Inhibitors 156 7.5 Nature of Kinase Inhibitors Based upon Binding 160 7.5.1 Type I Kinase Inhibitors and Their Design 160 7.5.2 Type II Kinase Inhibitors and Their Design 164 7.

5.3 Allosteric Kinase Inhibitors and Their Design 168 7.5.4 Covalent Kinase Inhibitors and Their Design 172 7.6 Conclusions 177 References 177 8 Protein X-Ray Crystallography in Structure-Based Drug Design 183 8.1 Introduction 183 8.2 Protein Expression and Purification 184 8.3 Synchrotron Radiation 185 8.

4 Structural Biology in Fragment-Based Drug Design 186 8.5 Selected Examples of Fragment-Based Studies 187 8.6 Conclusions 196 References 197 9 Structure-Based Design Strategies for Targeting G-Protein-Coupled Receptors (GPCRs) 199 9.1 Introduction 199 9.2 High-Resolution Structures of GPCRs 200 9.3 Virtual Screening Applied to the β 2 -Adrenergic Receptor 201 9.4 Structure-Based Design of Adenosine A 2A Receptor Antagonists 204 9.5 Structure-Guided Design of CCR5 Antagonists 207 9.

5.1 Development of Maraviroc from HTS Lead Molecules 207 9.5.2 Improvement of Antiviral Activity and Reduction of Cytochrome P450 Activity 208 9.5.3 Reduction of hERG Activity and Optimization of Pharmacokinetic Profile 209 9.5.4 Other CCR5 Antagonists 213 9.

6 Conclusion 213 References 213 Part Two Structure-Based Design of FDA-Approved Inhibitor Drugs and Drugs Undergoing Clinical Development 217 10 Angiotensin-Converting Enzyme Inhibitors for the Treatment of Hypertension: Design and Discovery of Captopril 219 10.1 Introduction 219 10.2 Design of Captopril: the First Clinically Approved Angiotensin-Converting Enzyme Inhibitor 220 10.3 Structure of Angiotensin-Converting Enzyme 225 10.4 Design of ACE Inhibitors Containing a Carboxylate as Zinc Binding Group 228 10.5 ACE Inhibitors Bearing Phosphorus-Based Zinc Binding Groups 231 10.5.1 Phosphonamidate-Based Inhibitors 232 10.

5.2 Phosphonic and Phosphinic Acid Derivatives: the Path to Fosinopril 233 10.6 Conclusions 234 References 235 11 HIV-1 Protease Inhibitors for the Treatment of HIV Infection and AIDS: Design of Saquinavir, Indinavir, and Darunavir 237 11.1 Introduction 237 11.2 Structure of HIV Protease and Design of Peptidomimetic Inhibitors Containing Transition-State Isosteres 239 11.3 Saquinavir: the First Clinically Approved HIV-1 Protease Inhibitor 241 11.4 Indinavir: an HIV Protease Inhibitor Containing the Hydroxyethylene Transition-State Isostere 246 11.5 Design and Development of Darunavir 251 11.

6 Design of Cyclic Ether Templates in Drug Discovery 252 11.7 Investigation of Cyclic Sulfones as P2 Ligands 255 11.8 Design of Bis-tetrahydrofuran and Other Bicyclic P2 Ligands 257 11.9 The "Backbone Binding Concept" to Combat Drug Resistance: Inhibitor Design Strategy Promoting Extensive Backbone Hydrogen Bonding from S2 to S2'' Subsites 259 11.10 Design of Darunavir and Other Inhibitors with Clinical Potential 263 11.11 Conclusions 266 References 266 12 Protein Kinase Inhibitor Drugs for Targeted Cancer Therapy: Design and Discovery of Imatinib, Nilotinib, Bafetinib, and Dasatinib 271 12.1 Introduction 271 12.2 Evolution of Kinase Inhibitors as Anticancer Agents 272 12.

3 The Discovery of Imatinib 274 12.4 Imatinib: the Structural Basis of Selectivity 275 12.5 Pharmacological Profile and Clinical Development 278 12.6 Imatinib Resistance 279 12.7 Different Strategies for Combating Drug Resistance 279 12.7.1 Nilotinib and Bafetinib: Optimizing Drug-Target Interactions 279 12.7.

2 Dasatinib: Binding to the Active Conformation (the First Example of Dual Abl/Src Inhibitors) 284 12.8 Conclusions 289 References 290 13 NS3/4A Serine Protease Inhibitors for the Treatment of HCV: Design and Discovery of Boceprevir and Telaprevir 295 13.1 Introduction 295 13.2 NS3/4A Structure 296 13.3 Mechanism of Peptide Hydrolysis by NS3/4A Serine Protease 299 13.4 Development of Mechanism-Based Inhibitors 300 13.5 Strategies for the Development of HCV NS3/4A Protease Inhibitors 303 13.6 Initial Studies toward the Development of Boceprevir 304 13.

7 Reduction of Peptidic Character 308 13.8 Optimization of P 2 Interactions 309 13.9 Truncation Strategy: the Path to Discovery of Boceprevir 312 13.10 The Discovery of Telaprevir 314 13.11 Simultaneous P1, P1'' , P2, P3, and P4 Optimization Strategy: the Path to Discovery of Telaprevir 316 13.12 Conclusions 319 References 319 14 Proteasome Inhibitors for the Treatment of Relapsed Multiple Myeloma: Design and Discovery of Bortezomib and Carfilzomib 325 14.1 Introduction 325 14.2 Discovery of Bortezomib 326 14.

3 Discovery of Carfilzomib 330 14.4 Conclusions 334 References 334 15 Development of Direct Thrombin Inhibitor, Dabigatran Etexilate, as an Anticoagulant Drug 337 15.1 Introduction 337 15.2 Coagulation Cascade and Anticoagulant Drugs 338 15.3 Anticoagulant Therapies 340 15.4 Structure of Thrombin 342 15.5 The Discovery of Dabigatran Etexilate 345 15.6 Conclusions 353 References 353 16 Non-Nucleoside HIV Reverse Transcriptase Inhibitors for the Treatment of HIV/AIDS: Design and Development of Etravirine and Rilpivirine 355 16.

1 Introduction 355 16.2 Structure of the HIV Reverse Transcriptase 357 16.3 Discovery of Etravirine and Rilpivirine 360 16.4 Conclusions 368 References 370 17 Renin In.