Protein surface recognition : approaches for drug discovery / edited by Ernest Giralt, Mark W. Peczuh, Xavier Salvatella. — Oxford : Wiley, 2011. – (58.17421/P967psr) |
Contents
Contents
Preface
List of Contributors
PART I Principles
1 The Discovery and Characterization of Protein-Protein Interactions
1.1 Introduction
1.2 Techniques to Identify Protein-Protein Interactions
1.3 Techniques to Characterize Protein-Protein Interactions
1.4 Structure and Dynamics of Protein Complexes
1.5 Protein-Protein Complexes as Therapeutic Targets
1.6 Conclusions
References
2 Biophysics of Protein-Protein Interactions
2.1 Introduction
2.2 Intermolecular Forces in Protein Recognition
2.3 Basic Binding Thermodynamics
2.4 Thermodynamically Driven Drug Design
2.5 Measurement of Binding Energetics
2.6 Structure-based Calculation of Protein Binding Energetics
2.7 Interfacial Water Molecules in Protein Recognition
2.8 The Linkage Between Binding and Conformational Equilibrium in Proteins
References
PART II Approaches
3 On the Logic of Natural Product Binding in Protein-Protein Interactivity
3.1 Introduction
3.2 Structural Logic
3.3 Functional Logic
3.4 The Need for Programmers
3.5 Compiling the NPPI Mapper
References
4 Interface Peptides
4.1 Interface Peptides Defined
4.2 Unmodified Peptides
4.3 Modified Peptides
4.4 Summary/Perspective
References
5 Inhibition of Protein-Protein Interactions by Peptide Mimics
5.1 Introduction
5.2 Inhibition of Calmodulin
5.3 Inhibition of HIV- 1 Fusion
5.4 Inhibition of the Nuclear Estrogen Receptor
5.5 Inhibition of the Bcl-xL/Bak Interaction
5.6 Inhibition of the p53/MDM2 Interaction
5.7 Miscellaneous Protein Targets
5.8 Conclusion
References
6 Discovery of Inhibitors of Protein-Protein Interactions by Screening Chemical Libraries
6.1 Introduction
6.2 Screening Strategies to Identify and Develop Antagonists of Protein-Protein Interactions
6.3 Mimetics of Common Protein Structure Motifs and Structure-based Design of Peptidomimetics
6.4 Conclusions and Outlook
References
PART III Techniques
7 High-throughput Methods of Chemical Synthesis Applied to the Preparation of Inhibitors of Protein-Protein Interactions 157
7.1 Introduction 157
7.2 Survey of High-throughput Organic Synthesis 159
7.3 Synthesis of 'Peptide-Inspired' Compounds and Libraries 162
7.4 Synthesis of 'Natural Product-Inspired' Compounds and Libraries 174
7.5 Diversity Oriented Synthesis (DOS) in the Discovery of PPI Inhibitors 188
7.6 Summary and Outlook 200
References 201
8 In Silico Screening
8.1 Introduction
8.2 Methods for Virtual Ligand Screening
8.3 Binding Site Characterization
8.4 Case Studies
8.5 Outlook and Conclusions
References
9.1 In Vitro Screening: Screening by Nuclear Magnetic Resonance
9.2 In Vitro Screening: Methods of High-throughput Screening
References
PART IV Case Studies
10 Case Study: Inhibitors of the MDM2-p53 Protein-Protein Interaction
10.1 MDM2-p53 Protein-Protein Interaction: A Case Study
10.2 Regulation of p53 by the MDM2-p53 Protein-Protein Interaction
10.3 Structural Basis of the MDM2-p53 Interaction
10.4 Design ofp53-based Peptides
10.5 Design of Nonpeptidic Small-Molecule Inhibitors of the MDM2-p53 Interaction
10.6 Challenges in the Design of Small Molecule Inhibitors of the MDM2-p53 Interaction
10.7 Reactivation of p53 by Inhibitors of the MDM2-p53 Interaction
10.8 Development of MDM2 Inhibitors as New Anticancer Drugs
10.9 Concluding Remarks
Acknowledgements
Disclosure Statement
References
11 Case Study: The Discovery of Potent LFA-1 Antagonists
11.1 Introduction
11.2 Structural, Molecular and Cellular Biologies of LFA-1
11.3 The Search for Small Molecule LFA-1 Antagonists
11.4 Screening Assays
11.5 Lead Identification and Optimization
11.6 Protein and Small Molecule Structure Activity Relationships (PSAR) in the LFA-1/ICAM-1 Interaction
11.7 Summary
References
Index