High-throughput molecular docking for lead discovery

CINF 75

Diane Joseph-McCarthy and Juan C. Alvarez. Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140
High-throughput virtual screening of large three-dimensional molecular databases enables the identification of novel small molecule drug leads for biologically relevant targets. Accurate molecular docking of small molecules to a target structure requires adequate sampling and accurate scoring of each library ligand in the target binding site. Our pharmacophore-based docking approach allows for efficient sampling of the ligand conformations and orientations in the target structure. The use of a fast scoring filter followed by a more rigorous scoring function to rank selected hits will be discussed. In particular, the utility of various scoring schemes for identifying viable leads in test cases as well as in a therapeutic target screen will be presented.