Catalytic Mechanism of Cytochrome P450 2D6 for 4-Hydroxylation of Aripiprazole： A QM/MM Study

Drug metabolism is an important issue in drug discovery. Understanding how a drug is metabolized in the body will provide helpful information for lead optimization. Cytochrome P450 2D6 （CYP2D6） is a key enzyme for drug metabolism and responsible for the metabolism of about one third marketed drugs. Aripiprazole is an atypical an- tipsychotic and metabolized by CYP2D6 to its hydroxylated form. In this study, a series of computational methods were performed to understand how CYP2D6 accomplishes the 4-hydroxylation of aripiprazole. Molecular docking and molecular dynamics simulations were first performed to prepare the initial conformations for QM/MM calcula- tions. The results revealed two possible conformations for the drug-CYP2D6 complex. The ONIOM method for QM/MM calculations was then carried out to show detailed reaction pathways for the CYP2D6-catalyzed aripipra- zole hydroxylation reaction, which demonstrated that the dominant reactive channel was electrophilic and involved an initial attack on the n-system of the dichlorophenyl group of aripiprazole to produce cation δ-complex. Further- more, the product complex for each conformation was thermodynamically stable, which is in good agreement with previous reports.