羟基化
细胞色素P450
CYP3A4型
化学
分子动力学
酶
分子力学
紫杉醇
机制(生物学)
对接(动物)
生物转化
立体化学
代谢途径
生物化学
计算化学
生物
癌症
遗传学
医学
认识论
哲学
护理部
作者
Dongxiao Yue,Hajime Hirao
标识
DOI:10.1021/acs.jcim.3c01630
摘要
Paclitaxel (PTX) is heralded as one of the most successful natural-product drugs for the treatment of refractory cancers. In humans, the hepatic metabolic transformation of PTX is primarily mediated by two cytochrome P450 enzymes (P450s): CYP3A4 and CYP2C8. The impact of P450 metabolism on the anticancer effectiveness of PTX is significant. However, the precise mechanism underlying selective P450-catalyzed reactions in PTX metabolism remains elusive. To address this knowledge gap, we conducted molecular docking and molecular dynamics simulations using multiple crystal structures of CYP3A4, which originally contained other ligands. These methods enabled us to determine the most plausible binding structure of PTX within the enzyme. By further employing hybrid quantum mechanics and molecular mechanics calculations, we successfully identified two primary pathways for the reaction between compound I (Cpd I) of CYP3A4 and PTX. One of these pathways involves the formation of an epoxide, while the other proceeds through a ketone intermediate.
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