Comparison of methods for in silico generation of solution-phase conformational ensembles
Knowledge of a ligand’s solution-phase conformational ensemble allows an additional level of rational design in pharmaceutical development. A recently developed technique for extracting conformations directly from NMR data now allows for a direct comparison between computational conformer generation and the real ensembles.
This talk will discuss the quality of ensemble reproduction achieved by four widely used conformer generation tools (Freeform, MOE’s Low Mode MD, Xedex, and the CCDC’s conformer generator) over a test set of druglike molecules. Based on recent results in generation of extended versus folded conformers, explicit solvent molecular dynamics in Amber is also tested for comparison. All experimental ensembles are directly derived from NMR data.
It is concluded that explicit solvent molecular dynamics offers the best reproduction of NMR-derived solution phase conformational ensembles, although at vastly increased computational cost relative to dedicated conformer generation codes.