title: Modulating protein-protein interactions with small molecules: the importance of binding hotspots.
abstract: 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.
authors.affiliation: National Center for Biotechnology Information, National Institutes of Health, 8600 Rockville Pike, Building 38A, Bethesda, MD 20894, USA.
authors.forename: Ratna Rajesh
authors.initials: RR
authors.lastname: Thangudu
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Bryant
authors.forename: Anna R
authors.initials: AR
authors.lastname: Panchenko
authors.forename: Thomas
authors.initials: T
authors.lastname: Madej
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D011506:Proteins