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The interaction of a small molecule with a protein target depends on its ability to adopt a three-dimensional structure that is complementary. Therefore, complete and rapid prediction of the conformational space a small molecule can sample is critical for both structure- and ligand-based drug discovery algorithms such as small molecule docking or three-dimensional quantitative structure–activity relationships. Here we have derived a database of small molecule fragments frequently sampled in experimental structures within the Cambridge Structure Database and the Protein Data Bank. 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. Explicit fragments take into account correlations between multiple torsion bonds and effect of substituents on torsional profiles. A conformational ensemble for small molecules can then be generated by recombining fragment rotamers with a Monte Carlo search strategy. BCL::C onf  was benchmarked against other conformer generator methods including C onfgen , M oe , O mega  and RDK it  in its ability to recover experimentally determined protein bound conformations of small molecules, diversity of conformational ensembles, and sampling rate. BCL::C onf  recovers at least one conformation with a root mean square deviation of 2 Å or better to the experimental structure for 99 % of the small molecules in the V ernalis  benchmark dataset. The ‘rotamer’ approach will allow integration of BCL::C onf  into respective computational biology programs such as R osetta .  Graphical abstract:   Conformation sampling is carried out using explicit fragment conformations derived from crystallographic structure databases. Molecules from the database are decomposed into fragments and most likely conformations/rotamers are used to sample correspondng sub-structure of a molecule of interest.Electronic supplementary material  The online version of this article (doi:10.1186/s13321-015-0095-1) contains supplementary material, which is available to authorized users.

BCL::Conf: small molecule conformational sampling using a knowledge based rotamer library