Discovery of small molecule inhibitors of protein-protein interactions using combined ligand and target score...

Docking experiments of multiple compounds typically focus on a single protein. However, other targets provide information about relative binding efficiencies that is otherwise lacking. We developed a docking strategy that normalized results in both the ligand and target dimensions. This was applied to dock 287 approved small drugs with 35 peptide-binding proteins, including 15 true positives. The combined docking score was normalized by drug and protein and by incorporating information on contact similarity to the template protein-peptide contacts. The 20 top ranking hits included 6 true positives, and three matches with suggestive evidence in the literature: the cardiac glycoside digitoxin may inhibit WW domain interactions, the 14-3-3 zeta protein may bind negatively charged ligands, and the nuclear receptor coactivator site may bind nuclear receptor agonists. Additionally, the Bcl-2 antiapoptotic protein is predicted to bind pargyline, and the antiapoptic p53 interacting protein MDM2 is suggested to bind clofazimine. These predictions represent starting points for the experimental development of PPI inhibitors based on an existing database of approved drugs and demonstrate that two-dimensional normalization improves docking efficiency.