Protein-Protein Interaction Interface (PPI)

Protein surfaces and interfaces are the physical contact regions between two or more protein molecules, essential for the formation of functional biological complexes (Scott et al., 2016, Nature Reviews Drug Discovery). These interfaces facilitate critical cellular processes such as signal transduction, molecular recognition, and enzymatic regulation (Arkin et al., 2014, Chemistry & Biology). In many disease states, including cancer and viral infections, protein-protein interactions (PPIs) are often hijacked or dysregulated, leading to pathological signaling (Wells & McClendon, 2007, Nature). Targeting these interfaces involves identifying "hot spots," which are specific clusters of residues that provide the majority of the binding free energy (Clackson & Wells, 1995, Science). Although historically viewed as "undruggable" due to their large and relatively flat surface areas, modern drug discovery has successfully developed small molecules and biologics to modulate these sites (Mabonga & Kappo, 2019, International Journal of Molecular Sciences). Drugs like Venetoclax work by binding to these interfaces to disrupt pro-survival complexes, thereby inducing apoptosis in cancer cells (Souers et al., 2013, Nature Medicine). Challenges in targeting protein interfaces include achieving high selectivity and overcoming the lack of deep binding pockets typical of traditional enzyme targets (Lu et al., 2020, Chemical Society Reviews).

Other names

Protein surfaceProtein interfaceProtein-protein interaction sitePPI site

Inhibition or stabilization of protein-protein interactions (PPIs) by binding to interface hot spots to modulate cellular signaling or complex formation.