Yamazoe Yasushi, Goto Takahiro, Tohkin Masahiro
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan; Food Safety Commission, Cabinet Office, Government of Japan, Akasaka Park Bldg. 22F 5-2-20 Akasaka, Minato-ku, Tokyo 107-6122, Japan; Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-City, Kanagawa, 210-9501, Japan.
Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
Drug Metab Pharmacokinet. 2019 Apr;34(2):113-125. doi: 10.1016/j.dmpk.2018.10.001. Epub 2018 Oct 15.
A hexagonal-grid based template system has been developed to a predicting tool of CYP3A4-mediated reactions through the reconstitution of the active site with the assembly of the ligands. Simultaneous interactions of flattened-shape ligands at two sites of CYP3A4, oxidizing- and triggering-sites, are essential ideas, which were supported in the simulation results of various ligands on the template. The interactions were accomplished with either uni-molecule bindings or bi-molecule bindings with ligands termed pro-metabolized and trigger molecules. The template shape was determined mainly through reciprocal comparisons of simulation results with available experiment data mainly on recombinant CYP3A4-mediated reactions of polyaromatic hydrocarbon (PAH) ligands. Through the applications of various PAH and non-PAH ligands on the template, couple region-specific interactions including mechanisms to facilitate ligand movement from the initial site to a place near heme-oxygen and to trigger of catalyses are envisioned. These are very effective tools to verify candidates of CYP3A4 ligands as the good or poor substrates. The bi-molecule binding idea also explains so called "cooperative bindings with activator/effector" as interactions with non-identical trigger molecules on this CYP3A4-template system, and also offers possible mechanisms of the non-linear kinetic behavior.
一种基于六边形网格的模板系统已被开发成一种预测工具，用于通过配体组装重构活性位点来预测CYP3A4介导的反应。扁平形状的配体在CYP3A4的两个位点（氧化位点和触发位点）同时发生相互作用是该系统的核心思想，这在模板上各种配体的模拟结果中得到了支持。这些相互作用通过与称为前代谢物和触发分子的配体进行单分子结合或双分子结合来实现。模板形状主要通过将模拟结果与主要关于重组CYP3A4介导的多环芳烃（PAH）配体反应的现有实验数据进行相互比较来确定。通过在模板上应用各种PAH和非PAH配体，可以设想出包括促进配体从初始位点移动到血红素氧附近位置以及触发催化作用机制在内的区域特异性相互作用。这些是验证CYP3A4配体是良好还是不良底物候选物的非常有效的工具。双分子结合的观点还解释了所谓的“与激活剂/效应器的协同结合”，即该CYP3A4模板系统上与不同触发分子的相互作用，并且还提供了非线性动力学行为的可能机制。
