Modulating Protein–Protein Interactions with Small Molecules: The Importance of Binding Hotspots

Author links open overlay panelRatna Rajesh Thangudu, Stephen H. Bryant, Anna R. Panchenko, Thomas Madej

The modulation of protein–protein interactions (PPIs) by small drug-like molecules is a relatively new area of research and has opened up new opportunities in drug discovery. However, the progress made in this area is limited to a handful of known cases of small molecules that target specific diseases. With the increasing availability of protein structure complexes, it is highly important to devise strategies exploiting homologous structure space on a large scale for discovering putative PPIs that could be attractive drug targets. Here, we propose a scheme that allows performing large-scale screening of all protein complexes and finding putative small-molecule and/or peptide binding sites overlapping with protein–protein binding sites (so-called "multibinding sites"). We find more than 600 nonredundant proteins from 60 protein families with multibinding sites. Moreover, we show that the multibinding sites are mostly observed in transient complexes, largely overlap with the binding hotspots and are more evolutionarily conserved than other interface sites. We investigate possible mechanisms of how small molecules may modulate protein–protein binding and discuss examples of new candidates for drug design.

► PPIs are attractive targets for drug design. ► Structure databases have a wealth of information about molecular interactions. ► We searched by homology for sites that bind both proteins and small molecules. ► We have found over 60 protein families with putative multibinding sites. ► The available structure evidence simplifies the virtual ligand screening process.