Abstract
Oseltamivir (OTV) is widely used in the treatment of both influenza virus A and B infections. Additionally, OTV is an effective antiviral drug in treating the 2009 A ( H1N1 ) influenza virus. Clinical studies concluded that OTV is readily extensively converted to the active carboxylate metabolite after oral administration. In order to investigate the metabolism mechanism of OTV, we carried out density functional theory (DFT) quantum mechanical calculations. The molecule orbital (MO) theory and natural population analysis (NPA) were also employed to help understanding the reaction mechanism. All possible reaction pathways for OTV metabolism are considered, involving hydrolysis of ester and amide. Two mechanisms were considered in this work, viz. concerted mechanism and stepwise mechanism. Our results indicate the stepwise mechanism is more favorable in both hydrolysis reactions and the rate-determining stage is the formation of the tetrahedral intermediate. In addition, the hydrolysis reactions can be assisted by substrate NH2 group and solvent water molecules. The substrate-assisted mechanism for the formation of the carboxylate metabolite is the most favorable one.
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