Automated generation of MCSS-derived pharmacophoric DOCK site points for searching multiconformation databases.

All docking methods employ some sort of heuristic to orient the ligand molecules into the binding site of the target structure. An automated method, MCSS2SPTS, for generating chemically labeled site points for docking is presented. MCSS2SPTS employs the program Multiple Copy Simultaneous Search (MCSS) to determine target-based theoretical pharmacophores. More specifically, chemically labeled site points are automatically extracted from selected low-energy functional-group minima and clustered together. These pharmacophoric site points can then be directly matched to the pharmacophoric features of database molecules with the use of either DOCK or PhDOCK to place the small molecules into the binding site. Several examples of the ability of MCSS2SPTS to reproduce the three-dimensional pharmacophoric features of ligands from known ligand-protein complex structures are discussed. In addition, a site-point set calculated for one human immunodeficiency virus 1 (HIV1) protease structure is used with PhDOCK to dock a set of HIV1 protease ligands; the docked poses are compared to the corresponding complex structures of the ligands. Finally, the use of an MCSS2SPTS-derived site-point set for acyl carrier protein synthase is compared to the use of atomic positions from a bound ligand as site points for a large-scale DOCK search. In general, MCSS2SPTS-generated site points focus the search on the more relevant areas and thereby allow for more effective sampling of the target site. Copyright 2003 Wiley-Liss, Inc.