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Catalytic Mechanism of Cytochrome P450 2D6 for 4-Hydroxylation of Aripiprazole: A QM/MM Study
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作者 Rongwei Shi Weihua Li +1 位作者 Guixia Liu Yun Tang 《Chinese Journal of Chemistry》 SCIE CAS CSCD 2013年第9期1219-1227,共9页
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 d... 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. 展开更多
关键词 ARIPIPRAZOLE CYP2D6 QM/MM hydroxylation reaction oniom method
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