Structural Biology in Drug Discovery Methods Techniques and Practices 1st Edition by Jean Paul Renaud ISBN 1118681010 9781118681015

Part I: Overview, Concepts, and Approaches

1. The Evolving Role of Structural Biology in Drug Discovery

• 1.1 Introduction
• 1.2 The Expanding Toolbox of Structural Biology for Drug Discovery
• 1.3 The Various Uses of Structural Biology in Drug Discovery
• 1.4 Evolving Drugs and Targets
• 1.5 Current Trends and Perspectives
• References

2. A Structural View on Druggability: Experimental and Computational Approaches

• 2.1 Introduction
• 2.2 Views on Target Druggability
• 2.3 In Silico Methods for Druggability Assessment of Targets with Well-Defined Pockets
• 2.4 Experimental Methods for Druggability Assessment
• 2.5 A Challenge for Druggability Predictions: Protein–Protein Interactions
• 2.6 Perspective
• References

3. Structural Chemogenomics: Profiling Protein–Ligand Interactions in Polypharmacological Space

• 3.1 Introduction
• 3.2 Simultaneously Targeting Multiple Proteins Can Be More Efficient in Disrupting Disease Mechanism
• 3.3 Computer-Aided Approaches for Profiling Bioactivities of Ligands
• 3.4 Applications
• 3.5 Conclusion
• References

4. Fragment-Based Ligand Discovery

• 4.1 Introduction
• 4.2 The Evolution of FBLD
• 4.3 The FBLD Process
• 4.4 Fragment Libraries
• 4.5 Maintaining a Fragment Library
• 4.6 Fragment Screening
• 4.7 Integrating Fragments with Other Compounds
• 4.8 Validating Fragment Hits: Comparing Methods
• 4.9 Fragment Hit Rates
• 4.10 Determining Structures of Fragment: Protein Complexes
• 4.11 Fragment Evolution
• 4.12 Concluding Remarks
• Acknowledgments
• References

5. Combining Structural, Thermodynamic, and Kinetic Information to Drive Hit-to-Lead Progression

• 5.1 Introduction
• 5.2 The Role of Thermodynamics in Hit to Lead
• 5.3 The Role of Kinetics in Hit to Lead
• 5.4 Summary
• References

6. Allostery as Structure-Encoded Collective Dynamics: Significance in Drug Design

• 6.1 Introduction
• 6.2 Computational Methods
• 6.3 Applications
• 6.4 Future Directions and Conclusion
• References

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Part II: Tool

7. Biophysical Assessment of Target Protein Quality in Structure-Based Drug Discovery

• 7.1 Biophysical Methods in Drug Discovery
• 7.2 Case Study I: Micro-Inhomogeneity
• 7.3 The Role of Biophysical Methods in the Optimization of Protein Crystallization
• 7.4 Case Study II: Minimizing Macro-Inhomogeneity
• 7.5 Outlook and Concluding Remarks: Requirements for Upcoming Biophysical Methods
• Acknowledgment
• References

8. An Industrial Perspective on Protein–Ligand Complex Crystallization

• 8.1 Introduction to Co-Crystal Structures and Drug Development
• 8.2 Basics of X-Ray Analysis of Co-Crystals
• 8.3 Ligands
• 8.4 Preparing Protein for Successful Crystallization
• 8.5 Crystallization
• 8.6 Selecting Ligands for Crystallization
• 8.7 Methods for Obtaining Co-Crystals: Soaking and Co-Crystallization
• 8.8 Future Perspective
• Acknowledgment
• References

9. Membrane Protein Crystallization

• 9.1 Introduction
• 9.2 Membrane Protein Production
• 9.3 Amphipathic Manipulation of Membrane Proteins
• 9.4 Preparing Protein Samples for Crystallization
• 9.5 Membrane Protein Crystallization
• 9.6 Methods for Determining Membrane Protein Structures
• 9.7 Conclusion and Outlooks
• References

10. High-Throughput Macromolecular Crystallography in Drug Discovery: Evolving in the Midst of Revolutions

• 10.1 Introduction
• 10.2 Setting the Scene for Evolution and Revolutions
• 10.3 Baseline: The “Human, All Too Human” Workflow of Early MX for SBDD
• 10.4 First Wave of Automation Toward High-Throughput Operation: Robotics Without Refactoring
• 10.5 Second Wave of Automation: The Twin Tracks of In Situ Crystallography and Microcrystallography
• 10.6 An Emerging Third Wave of Automation: Serial Microcrystallography
• 10.7 From Diffraction Data to Structural Results: Evolving Best Practices
• 10.8 Conclusions and Outlook: Whither HTMX for Drug Discovery?
• Acknowledgments
• References

11. Assessment of Crystallographic Structure Quality and Protein–Ligand Complex Structure Validation

• 11.1 Introduction
• 11.2 Quality Parameters
• 11.3 Dataset Quality
• 11.4 Low-Resolution Structures
• 11.5 Possible Influence of Crystal Packing
• 11.6 Software Tools
• 11.7 Analysis of Quality Metrics
• 11.8 Conclusions
• Acknowledgments
• References

12. Complementary Information from Neutron Crystallography Studies

• 12.1 Introduction
• 12.2 Differences in Characteristics of X-Rays and Neutrons
• 12.3 A Brief History of Protein Neutron Crystallography
• 12.4 Facility, Neutron Source, and Detector
• 12.5 Current Status of Neutron Protein Crystallography
• 12.6 Method for Neutron Crystallography of Proteins
• 12.7 General Information Obtained from Neutron Crystallography
• 12.8 Use of Neutron Crystallography for the Structure Analysis of Protein Drug Targets
• 12.9 Use of Neutron Protein Crystallography for Drug Design
• 12.10 Future Perspectives of the Use of Neutron Crystallography for Drug Design
• References

13. Determination of Protein Structure and Dynamics by NMR: State of the Art and Application to the Characterization of Biotherapeutics

• 13.1 Introduction
• 13.2 Solution Structure Determination of Macromolecules by NMR
• 13.3 Assignment and Labeling Strategies
• 13.4 NMR and Dynamic Aspects
• 13.5 Biomolecular Dynamics by NMR
• 13.6 Intrinsically Disordered Proteins
• 13.7 Alternative Approaches for Non-Soluble Proteins
• 13.8 Optimized Strategies for the Study of Biomolecules in Solution
• 13.9 Conclusion
• References

14. NMR Studies of Protein–Small Molecule Interactions for Drug Discovery

• 14.1 Introduction
• 14.2 Early-Stage Discovery
• 14.3 Lead Optimization
• 14.4 Emerging Applications/Fields
• 14.5 Outlook
• References

15. Computational Structural Biology for Drug Discovery: Power and Limitations

• 15.1 Introduction
• 15.2 Converting PDB Entries into Full-Atom Models
• 15.5 Future Perspective
• Acknowledgments
• References

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Part III: Structure-Based Discovery in Some Important or Promising Targets and Therapeutic Families

16. The Role of Structural Biology in Kinase Inhibitor Drug Discovery Success

• 16.1 Protein Kinases and Their Structural Elements: A Dynamic Landscape for Drug Discovery
• 16.2 The Challenge of Selectivity and Drug Resistance: Design and Discovery of Afatinib, the First Irreversible Protein Kinase Inhibitor Approved for Cancer Treatment
• 16.3 When Structural Biology Drives Chemistry to Therapeutic Breakthrough: The Vemurafenib Case History
• 16.4 Second-Generation Anaplastic Lymphoma Kinase Inhibitors: The Discovery of the First-in-Class Drug Ceritinib
• 16.5 The Discovery of Type II Inhibitor Ponatinib: A Milestone in the Struggle Against the ABL Gatekeeper Resistant Mutation T315I
• 16.6 Protein Kinase Inhibitor Drug Discovery and Structural Biology: Future Perspective
• References

17. Serine Proteinases from the Blood Coagulation Cascade

• 17.1 Introduction
• 17.2 Thrombin
• 17.3 Factor Xa (FXa)
• 17.4 Factor VIIa (FVIIa)
• 17.5 Further Developments
• 17.6 Factor IXa
• 17.7 Factor XIa
• 17.8 Impact of Structure-Based Drug Design
• References

18. Epigenetic Proteins as Emerging Drug Targets

• 18.1 Introduction
• 18.2 Acetylation/Deacetylation
• 18.3 Methylation/Demethylation
• 18.4 Other Epigenetic Modifications
• 18.5 The Future of Epigenetic Drug Discovery
• Acknowledgments
• References

19. Impact of Recently Determined Crystallographic Structures of GPCRs on Drug Discovery

• 19.1 G Protein-Coupled Receptors as Pharmaceutical Targets
• 19.2 Topology and Classes of GPCRs
• 19.3 GPCR X-Ray Crystal Structures
• 19.4 Class A GPCR Small Ligand Binding Sites and Druggability
• 19.5 Class B GPCR X-Ray Crystal Structures
• 19.6 Class C GPCRs and Allosteric Modulators
• 19.7 GPCR Activation
• 19.8 Structure-Based Approaches to GPCR Drug Discovery
• 19.9 Conclusion
• References

20. Targeting Protein–Protein Interactions Perspective

• 20.1 Introduction
• 20.2 Detection and Analysis of PPIs
• 20.3 PPI Screening
• 20.4 Examples
• 20.5 Stapled Peptides
• 20.6 Alternatives to Small-Molecule Orthosteric Inhibition
• 20.7 Conclusion and Perspectives
• References

21. Mass Spectrometry-Based Strategies for Therapeutic Antibodies Extensive Characterization and Optimization (OptimAbs)

• 21.1 Introduction
• 21.2 Intact mAb Analysis
• 21.3 Middle-Up mAb Analysis
• 21.4 Bottom-Up Peptide Mapping for Primary Structure Assessment
• 21.5 Top-Down Approaches for mAb Sequencing
• 21.6 Hydrogen/Deuterium Exchange Mass Spectrometry
• 21.7 Native MS and Ion Mobility-Mass Spectrometry (IM-MS) for the Characterization of mAb/Ag Binding Stoichiometry and of Protein Conformation
• 21.8 From Optimized Antibodies (OptimAbs) to Optimized Antibody-Drug Conjugates (OptimADCs)
• 21.9 Concluding Remarks
• Acknowledgments
• References

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Part IV: Challenges and New Frontiers

22. Integrating Evolution of Drug Resistance into Drug Discovery: Lessons from the Viral Proteases of HIV-1 and HCV

• 22.1 Evolution of Antiviral Drug Resistance
• 22.2 Substrate Envelope in Drug Design
• 22.3 Protein Dynamics Is Key to Molecular Recognition
• 22.4 Robust Drug Design: Hitting Multiple Targets at a Time
• 22.5 Future Perspective: Integrating Evolution and Conformational Dynamics into Drug Design
• Acknowledgments
• References

23. A Comprehensive Review on Mycobacterium tuberculosis Targets and Drug Development from a Structural Perspective

• 23.1 Introduction
• 23.2 Tuberculosis
• 23.3 Mycobacterium tuberculosis
• 23.4 Tuberculosis Drug Discovery and Development
• 23.5 Conclusion and Perspectives
• References

24. Using Crystal Structures of Drug-Metabolizing Enzymes in Mechanism-Based Modeling for Drug Design

• 24.1 Structure-Based Modeling of Cytochrome P450s
• 24.2 Other Phase I Drug-Metabolizing Enzymes
• 24.3 Phase II Drug-Metabolizing Enzymes
• 24.4 Interplay Between Metabolism and Inhibition
• 24.5 Future Directions
• Acknowledgment
• References

25. Intrinsically Disordered Proteins: Targets for the Future?

• 25.1 Introduction
• 25.2 IDPs as Novel Drug Targets
• 25.3 Molecular Mechanisms of Drugs Targeting Ordered Proteins
• 25.4 Disorder-Based Rational Drug Design
• 25.5 Direct Targeting of IDPs/IDPRs
• 25.6 Targeting Functionally Misfolded IDPs: A Hypothesis
• 25.7 Targeting Intrinsically Disordered Structural Ensembles: α-Synuclein as an Illustration
• 25.8 Targeting Aggregating IDPs
• 25.9 Conclusions
• Acknowledgments
• References

26. Cryo-Electron Microscopy as a Tool for Drug Discovery in the Context of Integrative Structural Biology

• 26.1 Introduction
• 26.2 The Resolution Revolution
• 26.3 What Is Cryo-EM?
• 26.4 The Cryo-EM Single-Particle Analysis Workflow
• 26.5 Selected Case Studies
• 26.6 Summary and Conclusion
• References

27. Application of Hard-X-Ray Free-Electron Lasers for Static and Dynamic Processes in Structural Biology

• 27.1 Introduction: Overview of X-Ray Free-Electron Lasers
• 27.2 Comparison with Conventional X-Ray Crystallography
• 27.3 XFEL Structures: Successes Since 2009
• 27.4 Challenges in XFELs
• 27.5 Future Outlook
• 27.6 Conclusion