Privileged Substructures to Modulate Protein–Protein Interactions

Given the difficulties to identify chemical probes that can modulate protein–protein interactions (PPIs), actors in the field have started to agree on the necessity to use PPI-tailored screening chemical collections. However, which type of scaffolds may promote the binding of compounds to PPI targets remains unclear. In this big data analysis, we have identified a list of privileged chemical substructures that are most often observed within inhibitors of PPIs. Using molecular frameworks as a way to perceive chemical substructures with the combination of an experimental and a machine-learning based predicted data set of iPPI compounds, we propose a list of privileged substructures in the form of scaffolds and chemical moieties that can be substantially chemically functionalized and do not present any toxicophore nor pan-assay interference (PAINS) alerts. We think that such chemical guidance will be valuable for medicinal chemists in their attempt to identify initial quality chemical probes on PPI targets.