Interactive Technologies for Leveraging the Known Chemistry of Anchor Residues to Disrupt Protein Interactions

Success stories in drug discovery are mostly circumscribed to traditional targets that often have endogenous ligands. Little effort has gone into developing new approaches for designing small molecular weight inhibitors for the myriad of protein-protein interactions (PPIs) revealed by recent genomic, system and structural biology initiatives. PPIs have been very difficult to target with small molecules due to their diverse structure, chemistry and flexibility, as well as the lack of suitable chemical scaffolds. In fact, it has been reported that "hit" rates from traditional high throughput screening are ≪1%. Here, we review virtual screening resources and our own approach applying novel computational methods to develop interactive technologies to disrupt protein interactions. As an alternative to the conventional screening of historical or known compounds, our technology delivers novel compounds and an accurate docking method by leveraging the known chemistry of well-defined anchor residues in protein interactions and multi-component reaction chemotypes to design small-molecule inhibitor starting points. Our anchor-centric method predicts that roughly 50% of PPIs in the PDB are druggable, enabling a powerful tool for modulating selective signaling pathways for systems biology.