High throughput docking for library design and library prioritization

The prioritization of the screening of combinatorial libraries is an extrem ely important task for the rapid identification of tight binding ligands an d ultimately pharmaceutical compounds. When structural information for the target is available, molecular docking is an approach that can be used for prioritization. Here, we present the initial validation of a new rapid appr oach to molecular docking developed for prioritizing combinatorial librarie s. The algorithm is tested on 103 individual cases from the protein data ba nk and in nearly 90% of these cases docks the ligand to within 2.0 Angstrom of the observed binding mode. Because the mean CPU time is <5 s/mol, this approach can process hundreds of thousands of compounds per week. Furthermo re, if a somewhat less thorough search is performed, the search time drops to 1 s/mol, thus allowing millions of compounds to be docked per week and t ested for potential activity. <(c)> 2001WiIey-Liss, Inc.