Structure-based design of drugs and other bioactive molecules : tools and strategies / Arun K. Ghosh and Sandra Gemma.

Format:

Book

Author/Creator:

Ghosh, Arun K., Prof. Dr., author.

Language:

English

Subjects (All):

Drug development--Data processing.

Drug development.

Bioactive compounds--Analysis.

Bioactive compounds.

Biopolymers--Identification.

Biopolymers.

Genre:

Electronic books.

Field guides.

Physical Description:

1 online resource (476 pages) : illustrations

Place of Publication:

Weinheim, Germany : Wiley-VCH, 2014.

System Details:

text file

Summary:

Drug design is a complex, challenging and innovative research area. Structure-based molecular design has transformed the drug discovery approach in modern medicine. Traditionally, focus has been placed on computational, structural or synthetic methods only in isolation. This one-of-a-kind guide integrates all three skill sets for a complete picture of contemporary structure-based design. This practical approach provides the tools to develop a high-affinity ligand with drug-like properties for a given drug target for which a high-resolution structure exists. The authors use numerous examples of recently developed drugs to present "best practice" methods in structure-based drug design with both newcomers and practicing researchers in mind. By way of a carefully balanced mix of theoretical background and case studies from medicinal chemistry applications, readers will quickly and efficiently master the basic skills of successful drug design. This book is aimed at new and active medicinal chemists, biochemists, pharmacologists, natural product chemists and those working in drug discovery in the pharmaceutical industry. It is highly recommended as a desk reference to guide students in medicinal and chemical sciences as well as to aid researchers engaged in drug design today. Book jacket.

Contents:

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 1 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 Pepridomimetic 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)sutfonarmide-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-Eased 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 Protease me 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 136

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 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

5.1 Protein Expression and Purification 184

8.1 Synchrotron Radiation 185

8.2 Structural Biology m Fragment-Based Drug Design 186

8.3 Selected Examples of Fragment-Based Studies 187

8.4 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 β₂-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

9.5.1 Reduction of hERG Activity and Optimization of Pharmacokinetic Profile 209

9.5 Other CCR5 Antagonists 213

9.6 Conclusion 213

References 213

Part 2 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 Carboxylase 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 tor 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, Nilolinib, Bafetinib, and Dasatinib 272

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 Dasarinib: 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 P₂ 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 Inhibitor for the Treatment of Hypertension: Design and Discovery of Aliskiren 373

17.1 Introduction 373

17.2 Structure of Renin 373

17.3 Peptidic Inhibitors with Transition-State Isosteres 374

17.4 Peptidomimetic Inhibitors 376

17.5 Design of Peptidomimetic Inhibitors 380

17.6 Biological Properties of Aliskiren 393

17.7 Conclusions 393

References 394

18 Neuraminidase Inhibitors for the Treatment of Influenza; Design and Discovery of Zanamivir and Oseltamivir 397

18.1 Introduction 397

18.2 Discovery of Zanamivir 401

18.3 Discovery of Oseltamivir 403

18.4 Conclusions 407

References 408

19 Carbonic Anhydrase Inhibitors for the Treatment of Glaucoma: Design and Discovery of Dorzolamide 411

19.1 Introduction 411

19.2 Design and Discovery of Dorzolamide 412

19.3 Conclusions 418

References 418

20 β-Secretase Inhibitors for the Treatment of Alzheimer's Disease: Preclinical and Clinical Inhibitors 421

20.1 Introduction 421

20.2 β-Secretase and Its X-Ray Structure 422

20.3 Development of First Peptidomirnetic BACE Inhibitors 423

20.4 X-Ray Structure of Inhibitor-Bound BACE1 425

20.5 Design and Development of Selective Inhibitors 427

20.6 Design of Small-Molecule Inhibitors with Clinical Potential 431

20.7 GRL-8234 (18) Rescued Cognitive Decline in AD Mice 435

20.8 BACE1 Inhibitors for Clinical Development 436

20.8.1 Development of Clinical Inhibitor, AZD3839 436

20.8.2 Development of Iminopyrimidmone-Based BACE1 Inhibitors 440

20.9 Conclusions 443

References 444.

Notes:

Includes bibliographical references at the end of each chapters and index.

Description based on online resource; title from PDF title page (ebrary, viewed August 13, 2014).

Local Notes:

Electronic reproduction. Palo Alto, Calif. : ebrary, 2014. Available via World Wide Web. Access may be limited to ebrary affiliated libraries.

Other Format:

Print version: Ghosh, Arun K. Structure-based design of drugs and other bioactive molecules : tools and strategies.

OCLC:

884646529

Access Restriction:

Restricted for use by site license.