从定向进化和计算建模中构建富含sp3的多环化合物的生物催化策略
David A Vargas1, Xinkun Ren2, Arkajyoti Sengupta3
1Process Research and Development, Merck, Rahway, NJ, USA.
Nature chemistry
|February 14, 2024
概括
工程酶使复杂分子的高效合成能够用于药物发现. 这项研究开发了用于立体选择性循环的生物催化剂,为早期的药物研究创造了新的sp3丰富的支架.
科学领域:
- 生物催化和有机合成
- 药用化学和药物发现
背景情况:
- 酶工程为制药提供了高效的合成途径.
- 生物催化在复杂分子合成的早期药物发现中未得到充分利用.
研究的目的:
- 开发一种生物催化策略,用于合成富含sp3的多环化合物.
- 为了发展碳转移酶,用于对二烯的立体选择性分子内循环化.
主要方法:
- 酶进化以产生具有特定区域异构体选择性的碳转移酶.
- 结晶学和计算分析以阐明反应机制.
- 通过综合进化和理性设计扩展基质范围.
主要成果:
- 成功进化了两个碳转移酶,用于对二衍生物的立体选择性循环.
- 使用结构和计算方法阐明反应机制.
- 将生物催化剂的范围扩大到以前不反应的基质,展示了新的自然转化.
结论:
- 生物催化剂可以有效地用于产生复杂的分子支架,用于药物发现.
- 综合进化和理性酶设计加速了新型生物催化转换的发展.
- 产生的富含sp3的支架具有可取的特性,用于基于片段的药物发现.
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