Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, 980-8578, Japan; Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-ku, Kawasaki, 210-9501, Japan.
Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526 Japan; Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co, Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan.
Drug Metab Pharmacokinet. 2022 Aug;45:100451. doi: 10.1016/j.dmpk.2022.100451. Epub 2022 Feb 7.
A ligand-accessible space in the CYP2C9 active site was reconstituted as a fused grid-based Template with the use of structural data of the ligands. CYP2C9 Template generated has been developed as an evaluation system of CYP2C9 metabolism with the introduction of the idea of Trigger-residue initiated ligand-movement and fastening. Reciprocal comparison of the data of simulation on Template with experimental results suggested a unified way of the interaction of CYP2C9 and its ligands through the simultaneous plural-contact with Rear-wall of Template. CYP2C9 was expected to have a room for ligands between vertically standing parallel walls termed Facial-wall and Rear-wall. Both the walls were separated by a distance corresponding to 1.5-Ring (grid) diameter size, which was termed as Width-gauge. The results indicate that ligand sittings are stabilized through contacts with Facial-wall and the left-side border of Template including specific Position 29 or Left-end after Trigger-residue movement. In addition, Trigger-residue movement is suggested to force ligands to stay firmly in the active site and then initiate CYP2C9 reactions. Simulation experiments for over 500 reactions of CYP2C9 ligands supported the system established. Possible modes of enhanced catalyzes in bi-molecule bindings are also discussed.
在 CYP2C9 活性位点中，配体可进入的空间通过使用配体的结构数据被重建为融合的基于网格的模板。生成的 CYP2C9 模板已被开发为 CYP2C9 代谢的评估系统，引入了触发残基引发配体运动和固定的理念。模板上的模拟数据与实验结果的相互比较表明，通过与模板后墙的同时多接触，CYP2C9 及其配体之间的相互作用具有统一的方式。CYP2C9 有望在垂直排列的平行壁之间（称为面壁和后墙）有一个容纳配体的空间。这两面墙之间的距离对应于 1.5-环（网格）直径大小，称为宽度规。结果表明，配体的位置通过与面壁和包括特定位置 29 或触发残基运动后的左侧边界的模板左侧边界的接触而得到稳定。此外，触发残基运动被认为可以将配体牢固地固定在活性位点中，然后引发 CYP2C9 反应。对超过 500 种 CYP2C9 配体反应的模拟实验支持了所建立的系统。还讨论了双分子结合中增强催化的可能模式。
