Rational design of topographical helix mimics as potent inhibitors of protein-protein interactions

Protein-protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small molecule scaffolds that reproduce the relative positioning and disposition of important binding residues, termed "hotspot residues", have been shown to successfully inhibit specific protein complexes. Although this strategy has led to development of novel synthetic inhibitors of protein complexes, often direct mimicry of natural amino acid residues does not lead to potent inhibitors. Experimental screening of focused compound libraries is used to further optimize inhibitors but the number of possible designs that can be efficiently synthesized and experimentally tested in academic settings is limited. We have applied the principles of computational protein design to optimization of nonpeptidic helix mimics as ligands for protein complexes. We describe the development of computational tools to design helix mimetics from canonical and noncanonical residue libraries and their application to two therapeutically important protein-protein interactions: p53-MDM2 and p300-HIF1α. The overall study provides a streamlined approach for discovering potent peptidomimetic inhibitors of protein-protein interactions.