BHB: A simple knowledge-based scoring function to improve the efficiency of database screening

A new knowledge-based scoring function was developed in this work to facilitate the rapid ranking of ligands in databases. The acronym of the method is BHB based on the descriptors it utilizes: buriedness, hydrogen bonding, and binding energy. Receptor buriedness is a measure of how well molecules occupy the binding pocket in comparison to known high-affinity ligands or, alternatively, whether they have contact with identified residues in the pocket. 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 using the optimized bound and free solvent conformations of the ligand-receptor system. The information necessary for the scoring function can ideally be gleaned from the 3D structure of the receptor-ligand complex. Alternatively, the descriptors can be derived from the 3D structure of the unbound receptor, provided this receptor has a known ligand that binds to the given site with nanomolar activity. We show that the new scoring functions provide up to 12 times improvement in enrichment compared to the popular commercial docking program GOLD.