Protein-protein interactions (PPIs) are the physical contacts established between two or more protein molecules as a result of biochemical events and/or electrostatic forces. PPIs are fundamental to almost all biological processes, including signal transduction, cellular structure, and metabolic regulation. In drug discovery, targeting PPIs offers opportunities to modulate complex biological pathways that are often inaccessible to traditional small-molecule drugs. PPIs comprise large flexible surfaces that are difficult to target by small molecules, and are more often the target of biologics. PPIs can be exploited by molecular glues that enhance interactions and PROTACs (proteolysis-targeting chimeras) that induce protein degradation. Peptides and macrocycles can also be effective at targeting broad surfaces.
Importance in Computational Drug Discovery:
- Expands the range of druggable targets by enabling intervention in pathways previously considered “undruggable.”
- Facilitates the design of molecules (small molecules, peptides, or biologics) that can disrupt or stabilize specific PPIs.
- Supports virtual screening, molecular docking, and molecular dynamics simulations tailored to large, often flat or flexible PPI interfaces.
- Enables prediction and mapping of PPI networks, aiding in target identification and validation.
- Assists in the rational design of inhibitors, stabilizers, or molecular glues for therapeutic intervention.
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