Structural ensemble in computational drug screening

Importance of the field: Structure-based in silico drug screening is now widely used in drug development projects. Structure-based in silico drug screening is generally performed using a protein–compound docking program and docking scoring function. Many docking programs have been developed over the last 2 decades, but their prediction accuracy remains insufficient. Areas covered in this review: This review highlights the recent progress of the post-processing of protein–compound complexes after docking. What the reader will gain: These methods utilize ensembles of docking poses of compounds to improve the prediction accuracy for the ligand-docking pose and screening results. While the individual docking poses are not reliable, the free energy surface or the most probable docking pose can be estimated from the ensemble of docking poses. Take home message: The protein–compound docking program provides an arbitral rather than a canonical ensemble of docking poses. When the ensemble of docking poses satisfies the canonical ensemble, we can discuss how these post-docking analysis methods work and fail. Thus, improvements to the docking software will be needed in order to generate well-defined ensembles of docking poses.