基于网格的 CYP3A4 模板系统在理解大配体相互作用机制中的应用；CYP3A4 模板研究的第 4 部分,Drug Metabolism and Pharmacokinetics

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基于网格的 CYP3A4 模板系统在理解大配体相互作用机制中的应用；CYP3A4 模板研究的第 4 部分
Drug Metabolism and Pharmacokinetics ( IF 2.7 ) Pub Date : 2020-12-01 , DOI: 10.1016/j.dmpk.2020.06.008
Takahiro Goto ₁ , Yasushi Yamazoe ₂ , Masahiro Tohkin ₃

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CYP3A4 与大尺寸配体的催化相互作用已在我们之前使用多芳烃和类固醇配体的研究中建立的模板上进行了研究（DMPK 34：113-125 和 351-364 2019 年，2020 年印刷）。典型的 CYP3A4 底物包括红霉素、环孢菌素 A（约 1200 Da）、伊维菌素 B1a 和紫杉烷类都被成功应用，并且这些配体的区域选择性代谢在模板上被忠实地重建。这些结果表明 CYP3A4 模板在整个 CYP3A4 配体的加宽尺寸中的适用性。大环内酯类抗生素在宽度规中显示出不同程度的紧坐，这是一种适应措施。观察到的差异与金霉素、红霉素、克拉霉素和阿奇霉素的不同抑制/灭活潜力有关，建议 CYP3A4 模板也可作为药物相互作用机制的工具。在本研究中，根据抗肿瘤剂利匹韦林的模拟结果，在氧化位点附近的模板区域略有扩大。大环内酯相互作用也建议从模板左侧进入配体。各种大尺寸配体的实验确保了精制 CYP3A4 模板的广泛适用性。

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Applications of a grid-based CYP3A4 Template system to understand the interacting mechanisms of large-size ligands; part 4 of CYP3A4 Template study

Catalytic interactions of CYP3A4 with large-size ligands have been studied on the Template established in our previous studies using polyaromatic hydrocarbon and steroid ligands (DMPK 34: 113-125 and 351-364 2019 and in press 2020). Typical CYP3A4-substrates including erythromycin, cyclosporin A (ca.1200 Da), ivermectin B1a and taxanes were applied successfully and regioselective metabolisms of these ligands were reconstituted faithfully on Template. These results suggest the applicability of CYP3A4 Template throughout broadened sizes of CYP3A4 ligands. Macrolide antibiotics showed distinct degrees of tight sittings in Width-gauge, a tool for accommodation measure. The observed differences were associated with different inhibitory/inactivation potentials of troleandomycin, erythromycin, clarithromycin and azithromycin, suggesting CYP3A4 Template also as a tool for drug-interaction mechanisms. Slight expansion of Template area was made at near Site of oxidation from simulation results of antitumor agent, rilpivirine, in the present study. Ligand entry from left side of Template is also suggested from macrolide interactions. Broadened applicability of the refined CYP3A4 Template were assured with experiments with various large-size ligands.

更新日期：2020-12-01

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