Enrichment of druggable conformations from apo protein structures using cosolvent-accelerated molecular dynamics.

ABSTRACT: Here we describe the development of an improved workflow for utilizing experimental and simulated protein conformations in the structure-based design of inhibitors for anti-apoptotic Bcl-2 family proteins. Traditional structure-based approaches on similar targets are often constrained by the sparsity of available structures and difficulties in finding lead compounds that dock against flat, flexible protein-protein interaction surfaces. By employing computational docking of known small molecule inhibitors, we have demonstrated that structural ensembles derived from either accelerated MD (aMD) or MD in the presence of an organic cosolvent generally give better scores than those assessed from analogous conventional MD. Furthermore, conformations obtained from combined cosolvent aMD simulation

SUBMITTER: Kalenkiewicz A 

PROVIDER: S-EPMC4498304 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature