CYP2C9 structure-metabolism relationships: substrates, inhibitors, and metabolites.

The cytochrome P450 (CYP) family is composed of monooxygenases, which mediate the metabolism of xenobiotics and endogenous compounds. The characterization of the interactions between these enzymes and candidate drugs is an important part of the drug discovery process. CYP2C9, one isoform of the CYPs, mediates the oxidation of several important drugs. The aim of this work is to investigate the possibility to study inhibition and substrate interactions with CYP2C9, using docking and the site of metabolism predictions. The model compounds used for the study were the COX-2 inhibitor celecoxib and a series of 13 analogues known to be metabolized by CYP2C9. The results obtained using the two methods gave valuable information about important interactions of inhibitors and substrates with CYP2C9. The two methods could be used to predict the site of metabolism and to determine the productive docking pose for each compound. These predictions were verified by metabolite identification using LC/MS/MS after incubation with recombinant CYP2C9.