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剂量-反应-基于活动的DNA编码图书馆查
Patrick R Fitzgerald1, Wesley G Cochrane2, Brian M Paegel2,3
1Skaggs Doctoral Program in the Chemical and Biological Sciences, Scripps Research, La Jolla, California 92037, United States.
ACS medicinal chemistry letters
|September 22, 2023
概括
这项研究引入了使用光分裂的剂量反应DNA编码库 (DEL) 选. 这种方法通过展示光化学剂量依赖反应来证实查结果,提高药物发现效率.
科学领域:
- 生物化学 生物化学
- 药用化学 医学化学
- 药物发现 药物发现 药物发现
背景情况:
- 剂量反应数据增强了对选命中真实性的信心.
- DNA编码库 (DEL) 选是一种强大的工具,用于识别生物标的小分子调节器.
- 光化学方法可以精确控制化合物释放和度.
研究的目的:
- 为了证明剂量反应固相DNA编码库 (DEL) 选.
- 为了验证光化学剂量反应DEL查对优先考虑药物线索的有用性.
- 使用这种新的查方法,评估命中率并识别抗Xa因子 (FXa) 和自毒素 (ATX) 的抑制剂.
主要方法:
- 一个拥有55,296个成员的DNA编码库 (DEL) 用光分裂诱导的化合物释放进行了选.
- 复合剂量由微流体滴中的不同紫外线强度调节.
- 对模型酶药物标进行了查:XA因子 (FXa) 和自毒素 (ATX).
主要成果:
- 对于FXa和ATX屏幕,观察到光化学剂量依赖的命中率.
- FXa的命中包括与已知的抑制剂一致的结构,其中四种化合物表现出抑制活性 (IC50值在4.2到19微米之间).
- 顶级ATX热量,包括二二胺醇和四化诺,被验证为抑制剂 (IC50值范围从1到13μM).
结论:
- 光化学剂量-反应DEL选有效地优先考虑合成的命中.
- 这种方法提高了DEL活动中领先识别的效率.
- 证明的剂量反应能力增加了对确定的命中药物的真实性的信心.
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