转氨酶变体的insilico工程用于增强 ACE 抑制剂前体的生物催化转化
Mohammad Asad1, Mohamed Usman1, Anisha Ashokan1
1Quantumzyme LLP, Bengaluru, India.
Journal of molecular graphics & modelling
|January 31, 2026
概括
这项研究引入了一个计算框架,用于设计新型转氨酶 (TA) 变体,用于合成ACE抑制剂中间体. 在的方法预测有希望的TA变体,以实现高效和立体选择性的不对称氨基化.
科学领域:
- 生物催化和酶工程 生物催化和酶工程
- 计算化学和分子建模计算化学和分子建模
- 药用化学和药物发现
背景情况:
- 传统的ACE抑制剂合成效率低下,涉及多个步骤和不良的立体选择性.
- 像L-homophenylalanine乙烯 (L-HPE) 这样的基质中间体对于ACE抑制剂的生产至关重要.
- 为不对称合成开发高效的生物催化剂是制药制造业的一个关键挑战.
研究的目的:
- 为设计和预测转胺酶 (TA) 变体提供一个计算框架.
- 确定能够催化乙烯2--4-甲酸乙烯 (OPBE) 转化为L-HPE的非对称氨基化的TA变体.
- 为合理的生物催化剂设计提供基础,用于制药中间体合成.
主要方法:
- 对Silicibacter转氨酶的同质模型.
- 使用分子对接,对11个活跃站点变体的in silico设计和选.
- 分子动力学模拟 (100 ns) 以评估酶基质复合物的稳定性.
- 使用雨抽样进行自由能量计算,以评估结合亲缘关系.
主要成果:
- 顶级变体 (SbTA10,SbTA01,SbTA11) 显示出稳定的酶基质复合体,具有有利的结合能 (-17.7 到 -20.8 kcal/mol).
- 一个复合的QZ得分确定SbTA10 (0.89),SbTA01 (0.88),和SbTA11 (0.85) 作为最有前途的变体.
- 自由能量配置文件显示了不同的基板保留特征,SbTA10显示了约束最小值 -10.2 kcal/mol.
结论:
- 计算框架成功地确定了OPBE到L-HPE转换的可信的转胺酶变体.
- 设计的变体具有有利于生物催化物的结构和能量特征.
- 这项研究为这些新型生物催化剂的实验验证提供了基础.
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