使用MAO酶的新型动态分辨率的thiazolo-Benzimidazolines使用MAO酶
Valentina Villamil1, Franco Vairoletti1,2, Ariel Tijman2,3,4
1Departamento de Química Orgánica, Laboratorio de Quimica Farmaceutica, Facultad de Quimica, Universidad de la República, Gral Flores 2124, Montevideo, Montevideo 11800, Uruguay.
ACS omega
|November 29, 2023
概括
通过使用工程化大肠杆菌实现了 thiazolo-benzimidazoline (TBIM) 异循环的酶动态分辨率. 这种方法成功地产生了纯的反体,为奇拉合成提供了一种新的方法.
科学领域:
- 生物催化和酶合成的生物催化.
- 有机化学和异环化合物
- 计算化学和分子建模
背景情况:
- 铁醇-胺醇 (TBIM) 杂环是药物化学中的重要支架.
- 获得纯净TBIM衍生物的有效方法是有限的.
- 酶动态分辨率为奇拉合成提供了一种可持续和选择性的方法.
研究的目的:
- 开发一种酶动态分辨率,用于种族TBIM异循环.
- 为了确定最佳的反应条件和评估基质范围.
- 阐明调节酶选择性的分子相互作用.
主要方法:
- 使用表达MAO-N D11酶的大肠杆菌进行全细胞生物催化.
- 选辅溶剂 (例如,DMF) 以优化反应产量和反体过量 (ee).
- 立体化学预测,对接和分子动力学 (MD) 模拟的初始计算.
主要成果:
- 通过使用DMF作为辅溶剂,成功地实现了种族性TBIM (2a) 的动态分离,产生了44%的产量和94%的eE的 (+) -enantiomer.
- 对11种替代的TBIM类似物进行的调查显示,非替代的2a提供了最好的结果.
- 替代效应显示,5替代的TBIM表现优于4替代的TBIM,小的电子捐赠组是有利的.
- MD模拟表明,2a的两种酶体都表现出有利的结合,这表明酶的入口道也影响了选择性.
结论:
- 这项研究报告了第一个TBIM异循环的酶动态分辨率.
- MAO-N D11酶显示出对TBIM衍生物的酶选择合成具有显著的潜力.
- 计算方法为酶基质相互作用和选择性决定因素提供了宝贵的见解.
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