Abstract The metallofullerenol Gd@C82(OH)22 is regarded as a potential anti-tumor therapeutic due to its metastasis inhibition in numerous experiments. As a promising nanodrug, the toxicity of Gd@C82(OH)22 requires thorough assessment before substantial clinical application. In the present study, we focus on the interaction between Gd@C82(OH)22 and the cytochrome P450 (CYP) enzyme CYP2C8. CYP2C8 can metabolize more than 60 clinically-used drugs as well as numerous endogenous compounds and hence is a representative target for nanotoxicity. From all-atom molecular dynamics simulations and free energy calculations, we observe that Gd@C82(OH)22 binds favorably to the B C and F-G loops that are substrate recognition sites (SRS) in CYPs. Moreover, binding on these two loops blocks the openings of channels 2b, 2e and 4, three of the most common channels that allow substrates to access and egress from the deeply buried heme active site. We find that bindingis largely driven by electrostatic interactions, with the induced negative charge on the surface of Gd@C82(OH)22 interacting favorably with the positively charged B C and F-G loops and only modestly with the negatively charged K′-L loop.

中文翻译：

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金属富勒烯醇 Gd@C 82 (OH) 22 通过阻断底物通道和底物识别位点抑制 CYP2C8

摘要 金属富勒烯醇 Gd@C82(OH)22 因其在众多实验中的转移抑制作用而被认为是一种潜在的抗肿瘤治疗剂。作为一种有前途的纳米药物，Gd@C82(OH)22 的毒性需要在大量临床应用之前进行彻底评估。在本研究中，我们关注 Gd@C82(OH)22 与细胞色素 P450 (CYP) 酶 CYP2C8 之间的相互作用。CYP2C8 可以代谢超过 60 种临床使用的药物以及许多内源性化合物，因此是纳米毒性的代表性靶点。从全原子分子动力学模拟和自由能计算中，我们观察到 Gd@C82(OH)22 与作为 CYP 底物识别位点 (SRS) 的 BC 和 FG 环有利地结合。此外，绑定在这两个环上会阻塞通道 2b、2e 和 4 的开口，三个最常见的通道，允许底物进出深埋的血红素活性位点。我们发现结合在很大程度上是由静电相互作用驱动的，Gd@C82(OH)22 表面上的感应负电荷与带正电的 BC 和 FG 环相互作用，而与带负电的 K'-L 环仅适度相互作用。