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The molecular mechanism of P450-catalyzed amination of the pyrrolidine derivative of lidocaine: insights from multiscale simulations.
RSC Advances ( IF 3.9 ) Pub Date : 2021-08-16 , DOI: 10.1039/d1ra04564d Conger Wang 1 , Peng Wu 1 , Zhanfeng Wang 1 , Binju Wang 1
RSC Advances ( IF 3.9 ) Pub Date : 2021-08-16 , DOI: 10.1039/d1ra04564d Conger Wang 1 , Peng Wu 1 , Zhanfeng Wang 1 , Binju Wang 1
Affiliation
Nitrogen heterocycles are key and prevalent motifs in drugs. Evolved variants of cytochrome P450BM3 (CYP102A1) from Bacillus megaterium employ high-valent oxo-iron(iv) species to catalyze the synthesis of imidazolidine-4-ones via an intramolecular C-H amination. Herein, we use multi-scale simulations, including classical molecular dynamics (MD) simulations, quantum mechanical/molecular mechanical (QM/MM) calculations and QM calculations, to reveal the molecular mechanism of the intramolecular C-H amination of the pyrrolidine derivative of lidocaine bearing cyclic amino moieties catalyzed by the variant RP/FV/EV of P450BM3, which bears five mutations compared to wild type. Our calculations show that overall catalysis includes both the enzymatic transformation in P450 and non-enzymatic transformation in water solution. The enzymatic transformation involves the exclusive hydroxylation of the C-H bond of the pyrrolidine derivative of lidocaine, leading to the hydroxylated intermediate, during which the substrate radical would be bypassed. The following dehydration and C-N coupling reactions are found to be much favored in aqueous situation compared to that in the non-polar protein environment. The present findings expand our understanding of the P450-catalyzed C(sp3)-H amination reaction.
中文翻译:
P450催化利多卡因吡咯烷衍生物胺化的分子机制:来自多尺度模拟的见解。
氮杂环是药物中的关键和普遍的基序。来自巨大芽孢杆菌的细胞色素 P450BM3 (CYP102A1) 的进化变体采用高价氧代铁 (iv) 物种通过分子内 CH 胺化催化 4-4 咪唑烷酮的合成。在此,我们使用多尺度模拟,包括经典分子动力学(MD)模拟、量子力学/分子力学(QM/MM)计算和QM计算,揭示利多卡因轴承吡咯烷衍生物分子内CH胺化的分子机制由 P450BM3 的变体 RP/FV/EV 催化的环状氨基部分,与野生型相比具有五个突变。我们的计算表明,整体催化包括 P450 中的酶促转化和水溶液中的非酶促转化。酶促转化涉及利多卡因的吡咯烷衍生物的 CH 键的独家羟基化,产生羟基化的中间体,在此期间底物自由基将被绕过。与非极性蛋白质环境相比,发现以下脱水和 CN 偶联反应在水环境中更受青睐。本研究结果扩展了我们对 P450 催化的 C(sp3)-H 胺化反应的理解。
更新日期:2021-08-16
中文翻译:
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P450催化利多卡因吡咯烷衍生物胺化的分子机制:来自多尺度模拟的见解。
氮杂环是药物中的关键和普遍的基序。来自巨大芽孢杆菌的细胞色素 P450BM3 (CYP102A1) 的进化变体采用高价氧代铁 (iv) 物种通过分子内 CH 胺化催化 4-4 咪唑烷酮的合成。在此,我们使用多尺度模拟,包括经典分子动力学(MD)模拟、量子力学/分子力学(QM/MM)计算和QM计算,揭示利多卡因轴承吡咯烷衍生物分子内CH胺化的分子机制由 P450BM3 的变体 RP/FV/EV 催化的环状氨基部分,与野生型相比具有五个突变。我们的计算表明,整体催化包括 P450 中的酶促转化和水溶液中的非酶促转化。酶促转化涉及利多卡因的吡咯烷衍生物的 CH 键的独家羟基化,产生羟基化的中间体,在此期间底物自由基将被绕过。与非极性蛋白质环境相比,发现以下脱水和 CN 偶联反应在水环境中更受青睐。本研究结果扩展了我们对 P450 催化的 C(sp3)-H 胺化反应的理解。