Targeting Protein-Protein Interactions for Drug Discovery

Chapter 1: Exploring Protein–Protein Interactions: Concepts, Methods, and Implications

• • 1.1 General Concepts of Protein–Protein Interactions
• • 1.1.1 Definition of Protein–Protein Interactions
• • 1.1.2 Structural Properties of Protein–Protein Interactions
• • 1.1.3 Diverse Types of Protein–Protein Interactions
• • 1.1.3.1 Enzyme–Substrate Interactions
• • 1.1.3.2 Receptor–Ligand Interactions
• • 1.1.3.3 Antigen–Antibody Interactions
• • 1.1.3.4 Chaperone–Client Interactions
• • 1.1.3.5 Scaffold Interactions
• • 1.2 Functional Significance of Protein–Protein Interactions
• • 1.2.1 Cellular Signal Transduction
• • 1.2.2 Regulation of Gene Expression
• • 1.2.3 Immune Response
• • 1.2.3.1 Immune Cell Migration
• • 1.2.3.2 T-Cell Antigen Recognition and Activation
• • 1.2.3.3 B-Cell Antigen Recognition and Activation
• • 1.2.4 Protein Degradation Pathway
• • 1.2.5 Disease Mechanisms
• • 1.2.5.1 Cancer
• • 1.2.5.2 Neurodegenerative Diseases
• • 1.2.5.3 Infectious Disease
• • 1.3 Methods for Analyzing Protein–Protein Interactions
• • 1.3.1 Experimental Methods
• • 1.3.1.1 Structure Determination
• • 1.3.1.2 Affinity, Kinetics, and Thermodynamics Measurement
• • 1.3.1.3 Large-Scale PPI Network Mapping
• • 1.3.2 Computational Methods
• • 1.3.2.1 Sequence-Based Methods
• • 1.3.2.2 Structure-Based Methods
• • 1.3.2.3 Network-Based Methods
• • 1.4 Implications of the Basic Research on Protein–Protein Interactions
• • 1.4.1 Advancing Disease Understanding and Diagnosis
• • 1.4.2 Driving Target-Based Drug Discovery
• • 1.4.3 Fostering Innovations in Biotechnology
• • 1.5 Conclusions and Perspectives
• • References

Chapter 2: Overview of Drug Discovery Targeting PPI Systems

• • 2.1 Introduction
• • 2.2 Fundamentals of Protein–Protein Interactions
• • 2.2.1 Basic Principles of Protein Structure and Function
• • 2.2.2 Types of Protein–Protein Interactions
• • 2.2.3 Significance of PPIs in Cellular Processes and Disease Pathways
• • 2.3 Challenges in Targeting PPI Systems
• • 2.3.1 Structural Complexities of PPI Interfaces
• • 2.3.2 Dynamics and Flexibility of Protein Complexes
• • 2.3.3 Druggability Issues Associated with PPI Targets
• • 2.4 Approaches in Drug Discovery Targeting PPI Systems
• • 2.4.1 High-Throughput Drug Design (HTS) Methods
• • 2.4.2 Structure-Based Drug Design (SBDD) Techniques
• • 2.4.3 Fragment-Based Drug Discovery (FBDD) Strategies
• • 2.4.4 Computational Methods for Predicting PPI Inhibitors
• • 2.5 Case Studies and Success Stories
• • 2.5.1 BCL Family
• • 2.5.1.1 Bcl- 2
• • 2.5.1.2 Bcl-xL
• • 2.5.1.3 Mcl- 1
• • 2.5.2 p53–MDM 2
• • 2.5.3 XIAP/c-IAP 1
• • 2.5.4 Cd40-cd40l
• • 2.5.5 Cyclin-Dependent Kinase (CDK)
• • 2.5.6 Pd-/pd-l 1
• • 2.5.7 Hsp90-Cdc 37
• • 2.5.8 Menin-MLL
• • 2.5.9 Kras-SOS 1
• • 2.5.10 Keap1-Nrf2 PPI
• • 2.6 Conclusion
• • References

Chapter 3: Fluorescence Resonance Energy Transfer Technology and its Applications

• • 3.1 Introduction
• • 3.2 Mechanism of FRET
• • 3.3 Applications of FRET
• • 3.3.1 Molecular Interactions
• • 3.3.2 Conformational Changes
• • 3.3.3 Cellular Imaging
• • 3.3.4 Drug Discovery
• • 3.3.5 Clinical Diagnosis
• • 3.3.6 Structural Biology
• • 3.3.7 Materials Science
• • 3.3.8 Environmental and Agricultural Sciences
• • 3.4 Advantages and Limitations
• • 3.5 Recent Advances
• • 3.6 Conclusion
• • Acknowledgements
• • References

Chapter 4: Dissect Protein Interactions Using Mass Spectrometry

• • 4.1 Introduction
• • 4.2 Affinity Purification Coupled with Mass Spectrometry (AP-MS)
• • 4.3 Proximity Labeling
• • 4.4 Cross-linking Mass Spectrometry (XL-MS)
• • 4.5 Co-fractionation Coupled with Mass Spectrometry (CF-MS)
• • 4.6 Thermal Proximity Co-aggregation (TPCA)
• • 4.7 Limited Proteolysis–Mass Spectrometry (LiP–MS)
• • 4.8 Conclusion and Outlook
• • Acknowledgements
• • References

Chapter 5: Detection of Protein–Protein Interactions In Situ via Proximity Ligation Assay

• • 5.1 Introduction
• • 5.2 Implementations of Proximity Ligation Assay
• • 5.3 Applications of PLA for Detecting Protein–Protein Interactions
• • 5.4 Conclusions and Outlooks
• • Acknowledgments
• • References

Chapter 6: Application of Surface Plasmon Resonance in the Characterization of Protein–Protein Interactions

• • 6.1 Introduction
• • 6.1.1 Protein–Protein Interactions
• • 6.1.2 Principle of Surface Plasmon Resonance
• • 6.1.3 Advantage of SPR
• • 6.2 Applications of SPR Assays in PPIs Characterization
• • 6.2.1 SPR Application in Binary PPI Systems
• • 6.2.1.1 SPR Assay in Verifying and Measuring PPIs
• • 6.2.1.2 SPR-Guided Screening and Optimization in Drug Discovery
• • 6.2.1.3 SPR in the Validation of PPI Interface
• • 6.2.2 SPR Application in Ternary PPI Systems
• • 6.2.2.1 SPR-Based Epitope Competition Assays
• • 6.2.2.2 SPR-Based Drug Discovery of PPI Modulators
• • 6.2.2.3 SPR Applications in Targeted Protein Degradation
• • 6.3 Advantages and Limitations of SPR Application for PPIs
• • 6.4 Future Directions
• • References

Chapter 7: Computational Methods for Protein–Protein Interactions

• • 7.1 Introduction
• • 7.2 Protein–Protein Docking
• • 7.2.1 Sampling
• • 7.2.1.1 Traditional Search Algorithms
• • 7.2.1.2 Deep Learning-Based Search Algorithms
• • 7.2.2 Scoring
• • 7.2.2.1 Traditional Scoring Function
• • 7.2.2.2 Deep Learning-Based Scoring Function
• • 7.2.3 Template-based Docking
• • 7.3 End-to-end Structure Prediction
• • 7.4 CAPRI Experiments
• • 7.4.1 Casp13-capri
• • 7.4.2 Casp14-capri
• • 7.4.3 Casp15-capri
• • 7.5 Challenges and Future Directions
• • Acknowledgments
• • Author Contributions
• • References

Chapter 8: Foldamers as Inhibitors of Aberrant Protein–Protein Interactions

• • 8.1 Introduction
• • 8.2 The Evolution of Hamilton’s Oligopyridylamides
• • 8.3 Limitations of a Tedious Synthetic Route
• • 8.4 OPs as Antagonists of Neurodegeneration
• • 8.5 OPs Inhibit HIV Infection
• • 8.6 OPs Targeting Type II Diabetes
• • 8.7 OPs Targeting and Reactivating Mutant Protein in Cancer
• • 8.8 Novel Synthesis of OPs and Alzheimer’s Disease
• • 8.9 2d-fast
• • 8.10 OQ Foldamers – Structure and Discovery
• • 8.11 Synthesis of OQ Foldamers
• • 8.12 OQs as Modulators of Type II Diabetes-Related aPPIs
• • 8.13 Mechanistic Insights into OQ Manipulation of aPPIs
• • 8.14 Chemical Diversity and Structure Modulate Efficacy of OQs
• • 8.15 Modulation of Alzheimer’s Disease-Related Aβ
• • 8.16 OQs for the Modulation of Synucleinopathies
• • 8.17 Epilogue
• • Acknowledgement
• • References

Chapter 9: Application of Sulfonyl-γ-AApeptides for PPI Drug Discovery

• • 9.1 Introduction
• • 9.2 Application of Sulfonyl-γ-AApeptides
• • 9.2.1 Modulation of PPIs Involved in Cancer
• • 9.2.1.1 Inhibition of β-catenin/B-cell lymphoma 9 PPIs
• • 9.2.1.2 p53-MDM2/MDMX PPIs Inhibitor
• • 9.2.1.3 HIF-1α PPI’s Inhibitor
• • 9.2.2 Anti-Viral
• • 9.2.2.1 HIV Fusion Inhibitor
• • 9.2.2.2 Pan-Coronavirus Fusion inhibitor
• • 9.2.3 Aβ-Oligomerization Modulation
• • 9.2.4 Diabetes Therapeutics
• • 9.3 Future Directions/Conclusion
• • Acknowledgments
• • References

Chapter 10: Introduction of the Application of Stapled Peptides in Protein–Protein Interactions Drug Discovery and Their Successful Examples

• • 10.1 Introduction
• • 10.1.1 Stapled Peptides as a Solution to PPI Challenges
• • 10.1.2 Growing Importance of PPIs in Drug Discovery
• • 10.1.3 Early Development and Success of Stapled Peptides
• • 10.1.4 Overview of the Chapter
• • 10.2 Stapled Peptides: Structure Features and Benefits
• • 10.2.1 Importance of α-Helical Structures in PPIs
• • 10.2.2 Designing Stapled Peptides: Mechanism of Stapling
• • 10.2.3 Additional Stapling Strategies
• • 10.2.3.1 Lactamization Between Lysine and Glutamate/Aspartate
• • 10.2.3.2 Azide–Alkyne Cycloaddition
• • 10.2.3.3 C—H Activation
• • 10.2.3.4 Cys–Cys Initiated Stapling Strategy
• • 10.2.3.5 Tyrosine Stapling
• • 10.2.4 Advantages of Stapled Peptides in Drug Discovery
• • 10.2.4.1 Enhanced Proteolytic Stability
• • 10.2.4.2 Improved Cell Permeability
• • 10.2.4.3 Ability to Target Previously “Undruggable” PPIs
• • 10.2.4.4 Specificity and Affinity Considerations
• • 10.3 Successful Applications of Stapled Peptides in Drug Discovery
• • 10.3.1 Targeting the MDM2–p53 Interaction
• • 10.3.2 Targeting BCL-2 Family Proteins
• • 10.3.3 Targeting the β-Catenin/TCF Interaction
• • 10.3.4 Infectious Diseases
• • 10.3.5 Clinical Progress and Future Directions
• • 10.4 Challenges and Limitations
• • 10.4.1 Manufacturing and Cost Considera