Assessment of Conformational Ensemble Sizes Necessary for Specific Resolutions of Coverage of Conformational Space

The size of conformational ensembles required for regular coverage of the conformational space of druglike molecules was examined. Using the conformer generation program Omega, the number of regularly distributed conformers (NRC) of flexible compounds was determined as a function of the root-mean-square deviation (RMSD) resolution of coverage. A regression equation was developed predicting the NRC of a molecule as a function of RMSD. The model yielded R² of 0.91 for both training and test sets, which consisted of 3414 and 3352 compounds, respectively. Utilizing 14 504 ligands from the Protein Data Bank with experimentally determined 3-D conformations, the regression equation was applied to the estimation of the NRC and the success rate of reproduction of experimental conformations from a theoretical conformation ensemble as a function of RMSD and flexibility was explored.