Can we learn from active ligands to improve the efficiency of virtual screening? The BHB scoring function


Miklos Feher, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, Eugen Deretey, MDS Proteomics, 251 Atwell Drive, Toronto, ON M9W 7H4, Canada, and Samir Roy, Department of Chemistry, University of Calgary, 2500 University Drive, N.W, Calgary, AB T2N 1N4, Canada.
Scoring functions for virtual screening are usually optimized to work for diverse sets of compounds. The question we wanted to answer is whether it is possible to improve the performance of the scoring function once a few active ligands have been identified. In receptor docking, the scoring function has two utilities: ligand placement in the pocket and ranking docked solutions. In our work we separated the two tasks: the former was left to the docking program, while we developed a novel function for the latter role. This function is based on the buriedness of the ligand in the receptor pocket, possible hydrogen bonding interactions and calculated binding energy. Receptor buriedness is a measure of how well molecules occupy the binding pocket in comparison to known high-affinity ligands. The possibility of hydrogen bond formation is checked for selected residues that are recognized as being important in the binding of known ligands. The approximate binding energy is calculated from the thermodynamic cycle. The information necessary for the scoring function can ideally be gleaned from the 3D structure of the receptor-ligand complex or the 3D structure of the receptor and known active ligands that bind to the given site. We show that the new scoring functions provide up to 12 times improvement in enrichment compared to the popular commercial docking program GOLD.

Docking and Scoring
1:30 PM-5:20 PM, Sunday, August 22, 2004 Pennsylvania Convention Center -- 109B, Oral

Division of Computers in Chemistry

The 228th ACS National Meeting, in Philadelphia, PA, August 22-26, 2004