• aripiprazole;
  • CYP2D6;
  • QM/MM;
  • hydroxylation reaction;
  • ONIOM method


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 antipsychotic 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 calculations. 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 aripiprazole hydroxylation reaction, which demonstrated that the dominant reactive channel was electrophilic and involved an initial attack on the π-system of the dichlorophenyl group of aripiprazole to produce cation δ-complex. Furthermore, the product complex for each conformation was thermodynamically stable, which is in good agreement with previous reports.