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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| Main Authors | , |
|---|---|
| Format | eBook Book |
| Language | English |
| Published |
Wenheim
Wiley-VCH
2014
John Wiley & Sons, Incorporated |
| Edition | 1 |
| Subjects | |
| Online Access | Get full text |
| ISBN | 3527333657 9783527333653 |
| DOI | 10.1002/9783527665211 |
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| Abstract | 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 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 structurebased 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. |
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| AbstractList | 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 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 structurebased 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. |
| Author | Ghosh, Arun K. Gemma, Sandra |
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| Discipline | Medicine Pharmacy, Therapeutics, & Pharmacology |
| EISBN | 3527665242 9783527665242 3527665234 9783527665235 |
| Edition | 1 |
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| Notes | Includes bibliographical references and index |
| OCLC | 884646529 |
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| PublicationPlace | Wenheim |
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| Publisher | Wiley-VCH John Wiley & Sons, Incorporated |
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| Snippet | Drug design is a complex, challenging and innovative research area. Structure-based molecular design has transformed the drug discovery approach in modern... |
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| SubjectTerms | Analysis Bioactive compounds Biopolymers Drug development Drugs Drugs -- Structure-activity relationships Ligand binding (Biochemistry) Protease inhibitors |
| TableOfContents | 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 |
| Title | Structure-based design of drugs and other bioactive molecules : tools and strategies |
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