Identification and in silico prediction of metabolites of the model compound, tebufenozide by human CYP3A4 and CYP2C19

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• 作者：Naoki Shirotani^a ; Moe Togawa^a ; Shinichi Ikushiro^b ; Toshiyuki Sakaki^b ; Toshiyuki Harada^a ; Hisashi Miyagawa^a ; Masayoshi Matsui^c ; Hirohisa Nagahori^c ; Kazuki Mikata^c ; Kazuhiko Nishioka^c ; Nobuhiro Hirai^a ; Miki Akamatsu^a ; ^{akamatsu@kais.kyoto-u.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CYP ; cytochrome P450 ; HLM ; human liver microsome ; RLM ; rat liver microsome ; DFT ; density functional theory ; NADPH ; 尾-nicotinamide adenine dinucleotide phosphate reduced tetrasodium salt ; tR ; Retention time
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2015
• 出版时间：15 October 2015
• 年：2015
• 卷：23
• 期：20
• 页码：6594-6601
• 全文大小：962 K

文摘

The metabolites of tebufenozide, a model compound, formed by the yeast-expressed human CYP3A4 and CYP2C19 were identified to clarify the substrate recognition mechanism of the human cytochrome P450 (CYP) isozymes. We then determined whether tebufenozide metabolites may be predicted in silico. Hydrogen abstraction energies were calculated with the density functional theory method B3LYP/6-31G^∗. A docking simulation was performed using FRED software. Several alkyl sites of tebufenozide were hydroxylated by CYP3A4 whereas only one site was modified by 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 abstraction energy estimation, respectively.