Identification and in silico prediction of metabolites of tebufenozide derivatives by major human cytochrome P450 isoforms |
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Affiliation: | 1. Graduate School of Agriculture, Kyoto University, Kitashirakawa-oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan;2. Faculty of Engineering, Toyama Prefectural University, 5180, Kurokawa, Imizu-shi, Toyama 939-0398, Japan;1. Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China;2. Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China;1. Center for Toxicogenomics and Human Health, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal;2. LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France |
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Abstract: | Cytochrome P450 (CYP) enzymes constitute a superfamily of heme-containing monooxygenases. CYPs are involved in the metabolism of many chemicals such as drugs and agrochemicals. Therefore, examining the metabolic reactions by each CYP isoform is important to elucidate their substrate recognition mechanisms. The clarification of these mechanisms may be useful not only for the development of new drugs and agrochemicals, but also for risk assessment of chemicals. In our previous study, we identified the metabolites of tebufenozide, an insect growth regulator, formed by two human CYP isoforms: CYP3A4 and CYP2C19. The accessibility of each site of tebufenozide to the reaction center of CYP enzymes and the susceptibility of each hydrogen atom for metabolism by CYP enzymes were evaluated by a docking simulation and hydrogen atom abstraction energy estimation at the density functional theory level, respectively. In this study, the same in silico prediction method was applied to the metabolites of tebufenozide derivatives by major human CYPs (CYP1A2, 2C9, 2C19, 2D6, and 3A4). In addition, the production rate of the metabolites by CYP3A4 was quantitively analyzed by frequency based on docking simulation and hydrogen atom abstraction energy using the classical QSAR approach. Then, the obtained QSAR model was applied to predict the sites of metabolism and the metabolite production order by each CYP isoform. |
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Keywords: | CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 Tebufenozide derivatives metabolites Docking simulation Hydrogen atom abstraction energy CYP" },{" #name" :" keyword" ," $" :{" id" :" k0055" }," $$" :[{" #name" :" text" ," _" :" cytochrome P450 QSAR" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" quantitative structure-activity relationship DFT" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" density functional theory NADPH" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," _" :" β-nicotinamide adenine dinucleotide phosphate reduced tetrasodium salt SOM" },{" #name" :" keyword" ," $" :{" id" :" k0095" }," $$" :[{" #name" :" text" ," _" :" sites of metabolism retention time |
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