The three-dimensional conformation a small molecule can adopt is critical for its binding to a target protein. Therefore, rapid and accurate prediction of the conformational space of a small molecule is critical for both structure- and ligand-based drug discovery algorithms such as docking or quantitative structure-activity relationships, respectively. Here we have derived a database of small molecule fragments frequently sampled in experimental structures within the crystallographic structure database (CSD) and the protein databank (PDB). Likely conformations of these fragments are stored as rotamers in analogy to amino acid side chain rotamer libraries used for rapid sampling of protein conformational space � an approach that will allow integration of BCL::Conf into respective computational biology programs such as Rosetta or Scwrl. A conformational ensemble for small molecules can now be generated by recombining fragment rotamers with a Monte Carlo search strategy. BCL::Conf was benchmarked against other conformer generator methods including Moe, Confab, and Frog2, in its ability to recover native-like protein bound conformation of small molecules, diversity of conformational ensembles, and sampling rate. BCL::Conf recovers 97% of molecules within a root mean square deviation of 2� to the native conformation.  The rapid rotamer sampling approach allows integration into Rosetta suite of macromolecular modeling and drug design module of the online protein folding game, Foldit. Conformer generation using multiple threads allows easy integration into high-throughput docking experiments using RosettaLigand.

BCL:Conf A knowledge based ligand flexibility algorithm and application in computational drug discovery like online drug design game Foldit

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.