Large-Scale Validation of Mixed-Solvent Simulations to Assess Hotspots at Protein–Protein Interaction Interfaces

• DOI: 10.1021/acs.jcim.7b00487
• Publication Date: 2018-04-04T16:22:11Z
• Authors: Phani Ghanakota; Herman van Vlijmen; Woody Sherman; Thijs Beuming
• Keywords: Druggability; Interface (matter); Chemical space

The ability to target protein–protein interactions (PPIs) with small molecule inhibitors offers great promise in expanding the druggable space and addressing a broad range of untreated diseases. However, due their nature function interacting protein partners, PPI interfaces tend extend over large surfaces without typical pockets enzymes receptors. These features present unique challenges for inhibitor design. As such, determining whether particular interest could be pursued discovery strategy requires an understanding characteristics interface it has hotspots that can leveraged by molecules achieve desired potency. Here, we assess mixed-solvent molecular dynamic (MSMD) simulations detect at interfaces. MSMD using three cosolvents (acetonitrile, isopropanol, pyrimidine) were performed on test set 21 targets have been experimentally validated inhibitors. We compare MSMD, which includes explicit solvent full flexibility, simpler approach does not include dynamics or (SiteMap) find reveal additional information about these inhibit interface. In few cases did hotspots, explore shortcomings this technique propose future improvements. Finally, Interleukin-2 as example, highlight advantage detecting transient cryptic exists