Targeting Protein–Protein Interactions Perspective

Protein-protein interactions (PPIs) encompass a diverse range of molecular interfaces of high importance in biology. PPIs are classified as either obligate or transitory, although these perhaps represent two extremes of the spectrum. In 2005, the Wang group reported the structure-based design of spirooxindole-containing small molecules as a new class of potent small-molecule inhibitors of the murine double minute 2-p53 interaction. Structure-based or fragment-based drug design approaches have been particularly successful for protein systems where there is a good structural understanding of the key elements for recognition, affinity, and selectivity. The evidence so far demonstrates that finding bromodomain (BD) inhibitors outside of the BET family is achievable, whether in silico predictions deem the BDs to be difficult, intermediate, or druggable. The catalytic activity of many enzymes is modulated by PPIs, providing opportunities for drug discovery. Many protein complexes are dynamic, and pharmacological modulation can be achieved not only by PPI inhibition but also through their stabilization.