From Concepts to Inhibitors: A Blueprint for Targeting Protein-Protein Interactions.

Area of Science:

• Biochemistry
• Drug Discovery
• Structural Biology

Background:

• Protein-protein interactions (PPIs) were historically considered undruggable targets.
• Recent advances in rational design and high-throughput screening have changed this paradigm.
• Targeting PPIs is crucial for therapeutic intervention in various diseases.

Purpose of the Study:

• To review the concepts and approaches driving progress in targeting PPIs.
• To highlight strategies for designing inhibitors against challenging protein surfaces.
• To discuss the integration of computational methods, natural product insights, and novel screening techniques.

Main Methods:

• Computational dissection of protein surfaces for ligand design.
• Design of macrocycles and miniprotein ligands.
• Leveraging natural product-derived binding epitopes as templates.
• Developing protein structure mimics for rational inhibitor design.
• Merging constrained peptides with contemporary screening methods.

Main Results:

• Identification of tractable protein surfaces, exemplified by successful targeting of Ras.
• Development of computational strategies for designing small molecule and peptide-based inhibitors.
• Utilization of natural protein-protein binding interfaces to guide inhibitor design.
• Advancements in creating diverse ligand scaffolds with conformational control.

Conclusions:

• Targeting PPIs is a rapidly advancing field with significant therapeutic potential.
• A combination of computational, biochemical, and screening approaches is key to success.
• Future efforts will likely focus on further refining design principles and expanding screening capabilities for PPI inhibitors.