title: Investigation of MM-PBSA rescoring of docking poses.
abstract: Target-based virtual screening is increasingly used to generate leads for targets for which high quality three-dimensional (3D) structures are available. To allow large molecular databases to be screened rapidly, a tiered scoring scheme is often employed whereby a simple scoring function is used as a fast filter of the entire database and a more rigorous and time-consuming scoring function is used to rescore the top hits to produce the final list of ranked compounds. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approaches are currently thought to be quite effective at incorporating implicit solvation into the estimation of ligand binding free energies. In this paper, the ability of a high-throughput MM-PBSA rescoring function to discriminate between correct and incorrect docking poses is investigated in detail. Various initial scoring functions are used to generate docked poses for a subset of the CCDC/Astex test set and to dock one set of actives/inactives from the DUD data set. The effectiveness of each of these initial scoring functions is discussed. Overall, the ability of the MM-PBSA rescoring function to (i) regenerate the set of X-ray complexes when docking the bound conformation of the ligand, (ii) regenerate the X-ray complexes when docking conformationally expanded databases for each ligand which include "conformation decoys" of the ligand, and (iii) enrich known actives in a virtual screen for the mineralocorticoid receptor in the presence of "ligand decoys" is assessed. While a pharmacophore-based molecular docking approach, PhDock, is used to carry out the docking, the results are expected to be general to use with any docking method.
authors.affiliation: Wyeth Research Chemical and Screening Sciences 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Thompson
authors.forename: Christine
authors.initials: C
authors.lastname: Humblet
authors.forename: Diane
authors.initials: D
authors.lastname: Joseph-McCarthy
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D008968:Molecular Conformation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D008024:Ligands; D011506:Proteins; D054852:Small Molecule Libraries; D012997:Solvents