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

Abstract

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.