一个完整的立体异构小分子矩阵的DNA条形码
Christopher J Gerry1,2, Mathias J Wawer2, Paul A Clemons2
1Department of Chemistry and Chemical Biology , Harvard University , 12 Oxford Street , Cambridge , Massachusetts 02138 , United States.
Journal of the American Chemical Society
|June 12, 2019
概括
我们开发了一种新方法来创建复杂化学结构的多样化DNA编码库. 这种方法可以发现强效的候选药物,比如新的碳酸酶抑制剂.
科学领域:
- 合成有机化学
- 药物化学
- 化学生物学
背景情况:
- DNA编码库 (DEL) 的合成面临着将立体化学多样性和复杂性纳入其中的挑战.
- 现代合成有机化学能力在DEL建设中没有得到充分利用.
研究的目的:
- 设计,构建和验证一种新的DNA编码图书馆 (DOS-DEL-1),该图书馆由性2,3-非替代性亚丁和罗利丁组成.
- 展示一种基于支架的立体化学多样性和复杂性的DEL合成策略.
- 在药物发现屏幕上验证图书馆的实用性.
主要方法:
- 用于脚手架的立体特异性C-H结合.
- 改进了对DNA的Suzuki反应以提高图书馆质量.
- 坦尼摩多聚变相似性分析用于性能评估.
- 对胡卜过氧化酶和碳酸无水酶IX进行验证.
- 开发一个基于Poisson的数据分析统计框架.
主要成果:
- 构建DOS-DEL-1,一个拥有107,616个DNA条形码的化合物的库.
- 大多数图书馆成员表现出类似药物的物理化学特性.
- 图书馆与以多样性为导向的综合收藏更为相似.
- 通过验证查成功鉴定出强烈的碳酸酶抑制剂 (IC50=20. 168. 7nM).
结论:
- 开发的战略使得具有显著的立体化学多样性和复杂性的DELs的合成成为可能.
- 这种方法不需要新的DNA兼容化学,利用现有的合成方法.
- 经过验证的图书馆和查框架有助于有效的药物发现,例如强效抑制剂的识别.
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