Site of metabolism prediction on cytochrome P450 2C9: a knowledge-based docking approach.

A novel structure-based approach for site of metabolism prediction has been developed. This knowledge-based method consists of three steps: (1) generation of possible metabolites, (2) docking the predicted metabolites to the CYP binding site and (3) selection of the most probable metabolites based on their complementarity to the binding site. As a proof of concept we evaluated our method by using MetabolExpert for metabolite generation and Glide for docking into the binding site of the CYP2C9 crystal structure. Our method could identify the correct metabolite among the three best-ranked compounds in 69% of the cases. The predictive power of our knowledge-based method was compared to that achieved by substrate docking and two alternative literature approaches.