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.

细胞色素P450（CYP）酶构成了含血红素的单加氧酶的超家族。CYPs参与许多化学物质的代谢，例如药物和农用化学物质。因此，检查每种CYP同工型的代谢反应对于阐明其底物识别机制很重要。澄清这些机制不仅对开发新药和农用化学品有用，而且对化学品的风险评估也可能有用。在我们之前的研究中，我们鉴定了昆虫生长调节剂Tebufenozide的代谢物，该代谢物由两种人CYP亚型组成：CYP3A4和CYP2C19。在密度泛函理论水平上，分别通过对接模拟和氢原子抽象能估计，评估了替布非尼嗪每个位点对CYP酶反应中心的可及性和每个氢原子对CYP酶代谢的敏感性。在这项研究中，相同In silico预测方法应用于主要人CYP（CYP1A2、2C9、2C19、2D6和3A4）对tebufenozide衍生物的代谢。此外，使用经典的QSAR方法，基于对接模拟和氢原子提取能量，通过频率对CYP3A4代谢产物的产生率进行了定量分析。然后，将获得的QSAR模型应用于预测每种CYP同工型的代谢位点和代谢产物的产生顺序。