In silico peptide-directed ligand design complements experimental peptide-directed binding for protein-protein interaction modulator discovery.

Using the protein-protein interaction of Mcl-1/Noxa, two methods for efficient modulator discovery are directly compared. In silico peptide-directed ligand design is evaluated against experimental peptide-directed binding, allowing for the discovery of two new inhibitors of Mcl-1/Noxa with cellular activity. In silico peptide-directed ligand design demonstrates an in vitro hit rate of 80% (IC50 < 100 μM). The two rapid and efficient methods demonstrate complementary features for protein-protein interaction modulator discovery.