Structure-based computational approaches for small-molecule modulation of protein-protein interactions.

Abstract

Three-dimensional structures of proteins offer an opportunity for the rational design of small molecules to modulate protein-protein interactions. The presence of a well-defined binding pocket on the surface of protein complexes, particularly at their interface, can be used for docking-based virtual screening of chemical libraries. Several approaches have been developed to identify binding pockets that are implemented in programs such as SiteMap, fpocket, and FTSite. These programs enable the scoring of these pockets to determine whether they are suitable to accommodate high-affinity small molecules. Virtual screening of commercial or combinatorial libraries can be carried out to enrich these libraries and select compounds for further experimental validation. In virtual screening, a compound library is docked to the target protein. The resulting structures are scored and ranked for the selection and experimental validation of top candidates. Molecular docking has been implemented in a number of computer programs such as AutoDock Vina. We select a set of protein-protein interactions that have been successfully inhibited with small molecules in the past. Several computer programs are applied to identify pockets on the surface, and molecular docking is conducted in an attempt to reproduce the binding pose of the inhibitors. The results highlight the strengths and limitations of computational methods for the design of PPI inhibitors.