Small-molecule inhibitors of protein-protein interactions: how to mimic a protein partner.

This systematic review describes successful examples of small-molecule inhibitors of protein-protein interactions, and compares their binding strategies to those employed by the natural protein partners. It extends and updates an earlier survey of this type (Fry DC, Curr Prot Pep Sci 2008; 9: 240-7). From analysis of these systems, common themes and lessons are presented that may assist future drug discovery efforts involving targets in this class. One encouraging finding is that a wide scope appears to be allowed at these sites in terms of binding strategies and chemotypes, which suggests that the outlook for finding small-molecule protein-protein inhibitors is favorable.