Structure-based drug discovery : an overview /

Structure-based drug discovery : an overview /

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Bibliographic Details
Imprint:Cambridge, UK : RSC Pub., c2006.
Description:xvi, 261 p. : ill. ; 24 cm.
Language:English
Series:RSC biomolecular sciences
Subject:
Drug Design.
Models, Molecular.
Structure-Activity Relationship.
Drugs -- Design.
Drugs -- Structure-activity relationships.
Format: Print Book
URL for this record:http://pi.lib.uchicago.edu/1001/cat/bib/6006298
Hidden Bibliographic Details
Other authors / contributors:Hubbard, R. E.
Royal Society of Chemistry (Great Britain)
ISBN:9780854043514
0854043519
Notes:Includes bibliographical references and index.
Table of Contents:
  • Chapter 1. 3D Structure and the Drug Discovery Process
  • 1. Introduction
  • 2. The Drug Discovery Process
  • 2.1. Establishing a Target
  • 2.2. Hit Identification
  • 2.3. Hits to Leads
  • 2.4. Lead Optimisation
  • 2.5. Pre-Clinical Trials
  • 2.6. Clinical Trials
  • 2.7. Maintaining the Pipeline
  • 3. What is Structure-Based Drug Discovery?
  • 3.1. From Hype to Application
  • 3.2. Structural Biology
  • 3.3. Structure-Based Design
  • 3.4. Structure-Based Discovery
  • 4. The Evolution of the Ideas of Structure-Based Drug Discovery
  • 4.1. 1960s
  • 4.2. 1970s
  • 4.3. 1980s
  • 4.4. 1990s
  • 4.5. 2000s
  • 5. What isn't in this Book
  • 5.1. Drug Discovery Against GPCR Targets
  • 5.2. Protein-Protein Interactions
  • 5.3. Using Structural Models of ADMET Mechanisms
  • 5.4. Protein Therapeutics
  • 5.5. Other Targets for Structure-Based Drug Discovery
  • 6. Concluding Remarks
  • References
  • Chapter 2. Structure Determination - Crystallography for Structure-Based Drug Discovery
  • 1. What is X-ray Crystallography?
  • 2. What is Required to Produce a Crystal Structure?
  • 3. Crystallisability of Proteins
  • 4. How does the X-ray Data Relate to the Electron Density? - The Phase Problem
  • 5. Electron Density Map Interpretation and Atomic Model of the Protein
  • 6. Useful Crystallographic Terminology when Utilising Crystal Structures
  • 7. The Clone-to-Structure Process and SBDD
  • 8. Recent Technological Advances
  • 9. The Role of Crystal Structures in the Discovery Process
  • 10. The Optimal SBDD System
  • 11. Producing a Biologically Relevant Structure
  • 12. Phosphorylation
  • 13. Glycosylation - Balancing Solubility with Crystallisability
  • 14. Engineering Solubility
  • 15. Specific Crystal Packing Engineering
  • 16. Engineering Stability
  • 17. Use of Surrogate Proteins
  • 18. The Impact of Structural Genomics
  • References
  • Chapter 3. Molecular Modelling
  • 1. Introduction
  • 2. Methods
  • 2.1. Quantum Chemistry Methods
  • 2.1.1. Ligand Internal Energy
  • 2.1.2. Study of Reactivity
  • 2.1.3. Ligand-Receptor Interaction Energy
  • 2.2. Parametric Methods
  • 2.2.1. Force-Fields
  • 2.2.2. Empirical Scoring Functions
  • 2.2.3. Statistical Potentials
  • 2.3. Solvation
  • 2.4. Sampling Algorithms
  • 3. Applications
  • 3.1. Target Evaluation
  • 3.1.1. Target Druggability
  • 3.1.2. Structure Availability and Critical Assessment
  • 3.2. Hit Finding
  • 3.2.1. Docking
  • 3.2.2. De novo Design
  • 3.2.3. The Role of Chemoinformatics
  • 3.2.4. Integrative VS
  • 3.2.5. Template or Scaffold Hopping
  • 3.2.6. Target Hopping
  • 3.3. Hit to Lead
  • 3.3.1. Binding Mode Determination
  • 3.3.2. Improving the Potency of the Hit
  • 3.3.3. Modulation of ADMET properties
  • 4. Conclusion
  • References
  • Chapter 4. Applications of NMR in Structure-Based Drug Discovery
  • 1. Introduction
  • 1.1. The Role of NMR in SBDD
  • 2. Studying Ligand-Receptor Interactions by NMR
  • 2.1. Detecting Ligand Binding
  • 2.2. Ligand-Based and Receptor-Based Screening
  • 2.3. Ligand-Based Approaches
  • 2.3.1. Filtered Experiments
  • 2.3.2. Magnetization Transfer Experiments
  • 2.3.3. Fluorine-Detected Experiments
  • 2.3.4. Ligand Displacement by a Known Competitor
  • 2.4. Receptor-Based Approaches
  • 2.4.1. Selective Labeling Strategies
  • 2.4.2. Larger Proteins
  • 2.4.3. [superscript 13]C labeling
  • 2.5. Examples of NMR-Screening Approaches
  • 2.5.1. Stromelysin
  • 2.5.2. Jnk3
  • 2.5.3. DNA Gyrase
  • 3. NMR in Structure-Based Lead Optimization
  • 3.1. Practical Aspects of Ligand-Receptor Complexes
  • 3.1.1. Determining Which NMR Approach to Use
  • 3.1.2. Methods for Preparation of the Complex
  • 3.2. NMR Methods for Characterizing Bound Ligands
  • 3.2.1. NMR Approaches for Ligand-Receptor Complexes in Fast Exchange
  • 3.2.2. NMR Approaches for Ligand/Receptor Complexes in Slow Exchange
  • 3.3. Chemical-Shift-Based Approaches Combined with Docking
  • 4. Other Applications of NMR in SBDD
  • 4.1. NMR in Protein Production
  • 4.2. Protein Structure Determination by NMR
  • 5. Conclusion and Outlook
  • References
  • Chapter 5. Fragment Screening: An Introduction
  • 1. Introduction
  • 2. The Concept of Drug-Likeness
  • 3. The Evolution of Lead-Likeness and Fragment Screening
  • 4. Finding Fragments by Screening
  • 4.1. High Concentration Screening using a Biochemical Assay
  • 4.2. Biophysical and Direct Structure Determination Screening
  • 4.2.1. Screening by Crystallography
  • 4.2.2. Screening by Other Biophysical Methods
  • 5. The Design of Fragment Screening Sets
  • 6. Turning Fragment Hits into Leads
  • 6.1. Fragment Evolution
  • 6.2. Fragment Linking
  • 6.3. Fragment Self-Assembly
  • 6.4. Fragment Optimisation
  • 7. Summary
  • References
  • Chapter 6. Iterative Structure-Based Screening of Virtual Chemical Libraries and Factor Xa: Finding the Orally Available Antithrombotic Candidate LY517717
  • 1. Introduction
  • 2. Morphology of the Factor Xa Active Site
  • 3. Structure-Based Library Design
  • 4. Design Strategy for Factor Xa
  • 5. Introducing Oral Availability
  • 6. Non-Basic S1 Series
  • 7. Oral Antithrombotic Activity
  • 8. Conclusion
  • Acknowledgements
  • References
  • Chapter 7. Anti-Influenza Drugs from Neuraminidase Inhibitors
  • 1. Introduction
  • 2. Influenza Viruses
  • 3. Early Attempts to Discover Neuraminidase Inhibitors
  • 4. Neuraminidase Structure
  • 5. Structure-Based Discovery of Inhibitors
  • 5.1. Zanamivir
  • 5.2. Analogues of Zanamivir
  • 5.3. Oseltamivir
  • 5.4. BCX1812 (RWJ270201)
  • 5.5. A315675
  • 5.6. Benzoic Acid Frameworks
  • 6. Retrospective Analyses of Inhibitor-Binding
  • 7. Laboratory Studies of Inhibitor Resistant Variants
  • 8. Clinical Studies of Drug Resistance
  • 9. Drug Profiles
  • 9.1. Pharmacology
  • 9.2. Efficacy in Therapy
  • 9.3. Efficacy in Prophylaxis
  • 9.4. Safety
  • 9.5. Current Approval Status
  • 10. Conclusions
  • References
  • Chapter 8. Isoform Specificity: The Design of Estrogen Receptor-[beta] Selective Compounds
  • 1. Introduction
  • 2. Structure-Based Design Methodology
  • 2.1. Initial Considerations
  • 2.2. Docking Calculations
  • 2.3. Quantum Chemical Calculations
  • 2.4. Interpretation of Structural Information
  • 3. The Design of Aryl Diphenolic Azoles As ER[beta] Selective Agonists
  • 3.1. Phenyl and Naphthyl Isoxazoles
  • 3.2. Phenyl and Naphthyl Benzoxazoles
  • 4. Learning From and Moving Beyond the Genistein Scaffold
  • 4.1. Biphenyl Scaffolds
  • 4.2. Phenyl Napthalenes
  • 4.3. Constrained Phenyl-Naphthalene Analogs: Dibenzochromenes
  • 5. Evaluation of ER[beta] Selective Compounds in Biological Assays
  • 6. Conclusions
  • Acknowledgments
  • References
  • Subject Index
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