Structure-based design of drugs and other bioactive molecules : tools and strategies

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-akind guide integ...

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Bibliographic Details
Main Authors Ghosh, Arun K., Gemma, Sandra
Format eBook Book
LanguageEnglish
Published Wenheim Wiley-VCH 2014
John Wiley & Sons, Incorporated
Edition1
Subjects
Analysis
Bioactive compounds
Biopolymers
Drug development
Drugs
Drugs > Structure-activity relationships
Ligand binding (Biochemistry)
Protease inhibitors
Online AccessGet full text
ISBN3527333657
9783527333653
DOI10.1002/9783527665211

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Table of Contents:
  • 20 β-Secretase Inhibitors for the Treatment of Alzheimer's Disease: Preclinical and Clinical Inhibitors
  • 3.8 Peptidyl α-Ketoamide- and α-Ketoheterocycle-Based Inhibitors -- 3.8.1 Synthesis of α-Ketoamide and α-Ketoheterocyclic Templates -- 3.9 Design of Serine Protease Inhibitors Based Upon Heterocycles -- 3.9.1 Isocoumarin-Derived Irreversible Inhibitors -- 3.9.2 β-Lactam-Derived Irreversible Inhibitors -- 3.10 Reversible/Noncovalent Inhibitors -- 3.11 Conclusions -- References -- 4 Design of Proteasome Inhibitors -- 4.1 Introduction -- 4.2 Catalytic Mechanism of 20S Proteasome -- 4.3 Proteasome Inhibitors -- 4.3.1 Development of Boronate Proteasome Inhibitors -- 4.3.2 Development of β-Lactone Natural Product-Based Proteasome Inhibitors -- 4.3.3 Development of Epoxy Ketone-Derived Inhibitors -- 4.3.4 Noncovalent Proteasome Inhibitors -- 4.4 Synthesis of β-Lactone Scaffold -- 4.5 Synthesis of Epoxy Ketone Scaffold -- 4.6 Conclusions -- References -- 5 Design of Cysteine Protease Inhibitors -- 5.1 Introduction -- 5.2 Development of Cysteine Protease Inhibitors with Michael Acceptors -- 5.3 Design of Noncovalent Cysteine Protease Inhibitors -- 5.4 Conclusions -- References -- 6 Design of Metalloprotease Inhibitors -- 6.1 Introduction -- 6.2 Design of Matrix Metalloprotease Inhibitors -- 6.3 Design of Inhibitors of Tumor Necrosis Factor-α-Converting Enzymes -- 6.4 Conclusions -- References -- 7 Structure-Based Design of Protein Kinase Inhibitors -- 7.1 Introduction -- 7.2 Active Site of Protein Kinases -- 7.3 Catalytic Mechanism of Protein Kinases -- 7.4 Design Strategy for Protein Kinase Inhibitors -- 7.5 Nature of Kinase Inhibitors Based upon Binding -- 7.5.1 Type I Kinase Inhibitors and Their Design -- 7.5.2 Type II Kinase Inhibitors and Their Design -- 7.5.3 Allosteric Kinase Inhibitors and Their Design -- 7.5.4 Covalent Kinase Inhibitors and Their Design -- 7.6 Conclusions -- References -- 8 Protein X-Ray Crystallography in Structure-Based Drug Design
  • 11.4 Indinavir: an HIV Protease Inhibitor Containing the Hydroxyethylene Transition-State Isostere -- 11.5 Design and Development of Darunavir -- 11.6 Design of Cyclic Ether Templates in Drug Discovery -- 11.7 Investigation of Cyclic Sulfones as P2 Ligands -- 11.8 Design of Bis-tetrahydrofuran and Other Bicyclic P2 Ligands -- 11.9 The "Backbone Binding Concept" to Combat Drug Resistance: Inhibitor Design Strategy Promoting Extensive Backbone Hydrogen Bonding from S2 to S2' Subsites -- 11.10 Design of Darunavir and Other Inhibitors with Clinical Potential -- 11.11 Conclusions -- References -- 12 Protein Kinase Inhibitor Drugs for Targeted Cancer Therapy: Design and Discovery of Imatinib, Nilotinib, Bafetinib, and Dasatinib -- 12.1 Introduction -- 12.2 Evolution of Kinase Inhibitors as Anticancer Agents -- 12.3 The Discovery of Imatinib -- 12.4 Imatinib: the Structural Basis of Selectivity -- 12.5 Pharmacological Profile and Clinical Development -- 12.6 Imatinib Resistance -- 12.7 Different Strategies for Combating Drug Resistance -- 12.7.1 Nilotinib and Bafetinib: Optimizing Drug-Target Interactions -- 12.7.2 Dasatinib: Binding to the Active Conformation (the First Example of Dual Abl/Src Inhibitors) -- 12.8 Conclusions -- References -- 13 NS3/4A Serine Protease Inhibitors for the Treatment of HCV: Design and Discovery of Boceprevir and Telaprevir -- 13.1 Introduction -- 13.2 NS3/4A Structure -- 13.3 Mechanism of Peptide Hydrolysis by NS3/4A Serine Protease -- 13.4 Development of Mechanism-Based Inhibitors -- 13.5 Strategies for the Development of HCV NS3/4A Protease Inhibitors -- 13.6 Initial Studies toward the Development of Boceprevir -- 13.7 Reduction of Peptidic Character -- 13.8 Optimization of P2 Interactions -- 13.9 Truncation Strategy: the Path to Discovery of Boceprevir -- 13.10 The Discovery of Telaprevir
  • Structure-based Design of Drugs and Other Bioactive Molecules: Tools and Strategies -- Contents -- Preface -- 1 From Traditional Medicine to Modern Drugs: Historical Perspective of Structure-Based Drug Design -- 1.1 Introduction -- 1.2 Drug Discovery During 1928-1980 -- 1.3 The Beginning of Structure-Based Drug Design -- 1.4 Conclusions -- References -- Part One: Concepts, Tools, Ligands, and Scaffolds for Structure-Based Design of Inhibitors -- 2 Design of Inhibitors of Aspartic Acid Proteases -- 2.1 Introduction -- 2.2 Design of Peptidomimetic Inhibitors of Aspartic Acid Proteases -- 2.3 Design of Statine-Based Inhibitors -- 2.4 Design of Hydroxyethylene Isostere-Based Inhibitors -- 2.5 Design of Inhibitors with Hydroxyethylamine Isosteres -- 2.5.1 Synthesis of Optically Active α-Aminoalkyl Epoxide -- 2.6 Design of (Hydroxyethyl)urea-Based Inhibitors -- 2.7 (Hydroxyethyl)sulfonamide-Based Inhibitors -- 2.8 Design of Heterocyclic/Nonpeptidomimetic Aspartic Acid Protease Inhibitors -- 2.8.1 Hydroxycoumarin- and Hydroxypyrone-Based Inhibitors -- 2.8.2 Design of Substituted Piperidine-Based Inhibitors -- 2.8.3 Design of Diaminopyrimidine-Based Inhibitors -- 2.8.4 Design of Acyl Guanidine-Based Inhibitors -- 2.8.5 Design of Aminopyridine-Based Inhibitors -- 2.8.6 Design of Aminoimidazole- and Aminohydantoin-Based Inhibitors -- 2.9 Conclusions -- References -- 3 Design of Serine Protease Inhibitors -- 3.1 Introduction -- 3.2 Catalytic Mechanism of Serine Protease -- 3.3 Types of Serine Protease Inhibitors -- 3.4 Halomethyl Ketone-Based Inhibitors -- 3.5 Diphenyl Phosphonate-Based Inhibitors -- 3.6 Trifluoromethyl Ketone Based Inhibitors -- 3.6.1 Synthesis of Trifluoromethyl Ketones -- 3.7 Peptidyl Boronic Acid-Based Inhibitors -- 3.7.1 Synthesis of α-Aminoalkyl Boronic Acid Derivatives
  • 8.1 Introduction -- 8.2 Protein Expression and Purification -- 8.3 Synchrotron Radiation -- 8.4 Structural Biology in Fragment-Based Drug Design -- 8.5 Selected Examples of Fragment-Based Studies -- 8.6 Conclusions -- References -- 9 Structure-Based Design Strategies for Targeting G-Protein-Coupled Receptors (GPCRs) -- 9.1 Introduction -- 9.2 High-Resolution Structures of GPCRs -- 9.3 Virtual Screening Applied to the β2-Adrenergic Receptor -- 9.4 Structure-Based Design of Adenosine A2A Receptor Antagonists -- 9.5 Structure-Guided Design of CCR5 Antagonists -- 9.5.1 Development of Maraviroc from HTS Lead Molecules -- 9.5.2 Improvement of Antiviral Activity and Reduction of Cytochrome P450 Activity -- 9.5.3 Reduction of hERG Activity and Optimization of Pharmacokinetic Profile -- 9.5.4 Other CCR5 Antagonists -- 9.6 Conclusion -- References -- Part Two: Structure-Based Design of FDA-Approved Inhibitor Drugs and Drugs Undergoing Clinical Development -- 10 Angiotensin-Converting Enzyme Inhibitors for the Treatment of Hypertension: Design and Discovery of Captopril -- 10.1 Introduction -- 10.2 Design of Captopril: the First Clinically Approved Angiotensin-Converting Enzyme Inhibitor -- 10.3 Structure of Angiotensin-Converting Enzyme -- 10.4 Design of ACE Inhibitors Containing a Carboxylate as Zinc Binding Group -- 10.5 ACE Inhibitors Bearing Phosphorus-Based Zinc Binding Groups -- 10.5.1 Phosphonamidate-Based Inhibitors -- 10.5.2 Phosphonic and Phosphinic Acid Derivatives: the Path to Fosinopril -- 10.6 Conclusions -- References -- 11 HIV-1 Protease Inhibitors for the Treatment of HIV Infection and AIDS: Design of Saquinavir, Indinavir, and Darunavir -- 11.1 Introduction -- 11.2 Structure of HIV Protease and Design of Peptidomimetic Inhibitors Containing Transition-State Isosteres -- 11.3 Saquinavir: the First Clinically Approved HIV-1 Protease Inhibitor
  • 13.11 Simultaneous P1, P1', P2, P3, and P4 Optimization Strategy: the Path to Discovery of Telaprevir -- 13.12 Conclusions -- References -- 14 Proteasome Inhibitors for the Treatment of Relapsed Multiple Myeloma: Design and Discovery of Bortezomib and Carfilzomib -- 14.1 Introduction -- 14.2 Discovery of Bortezomib -- 14.3 Discovery of Carfilzomib -- 14.4 Conclusions -- References -- 15 Development of Direct Thrombin Inhibitor, Dabigatran Etexilate, as an Anticoagulant Drug -- 15.1 Introduction -- 15.2 Coagulation Cascade and Anticoagulant Drugs -- 15.3 Anticoagulant Therapies -- 15.4 Structure of Thrombin -- 15.5 The Discovery of Dabigatran Etexilate -- 15.6 Conclusions -- References -- 16 Non-Nucleoside HIV Reverse Transcriptase Inhibitors for the Treatment of HIV/AIDS: Design and Development of Etravirine and Rilpivirine -- 16.1 Introduction -- 16.2 Structure of the HIV Reverse Transcriptase -- 16.3 Discovery of Etravirine and Rilpivirine -- 16.4 Conclusions -- References -- 17 Renin Inhibitor for the Treatment of Hypertension: Design and Discovery of Aliskiren -- 17.1 Introduction -- 17.2 Structure of Renin -- 17.3 Peptidic Inhibitors with Transition-State Isosteres -- 17.4 Peptidomimetic Inhibitors -- 17.5 Design of Peptidomimetic Inhibitors -- 17.6 Biological Properties of Aliskiren -- 17.7 Conclusions -- References -- 18 Neuraminidase Inhibitors for the Treatment of Influenza: Design and Discovery of Zanamivir and Oseltamivir -- 18.1 Introduction -- 18.2 Discovery of Zanamivir -- 18.3 Discovery of Oseltamivir -- 18.4 Conclusions -- References -- 19 Carbonic Anhydrase Inhibitors for the Treatment of Glaucoma: Design and Discovery of Dorzolamide -- 19.1 Introduction -- 19.2 Design and Discovery of Dorzolamide -- 19.3 Conclusions -- References