通过电片选快速发现共价探头
Efrat Resnick, Anthony Bradley1,2, Jinrui Gan
1Department of Chemistry , Chemistry Research Laboratory , 12 Mansfield Road , Oxford OX1 3TA , U.K.
Journal of the American Chemical Society
|May 8, 2019
概括
发现强大的共价探测器是一个挑战. 这项研究引入了一种新的电粉碎片选方法,为以前未被准的酶如OTUB2和NUDT7产生选择性探针.
科学领域:
- 化学生物学
- 药物发现
- 基于碎片的选
背景情况:
- 协价探针提供更高的效能和持续时间, 但很难发现.
- 电友碎片虽然可能强大,但往往缺乏选择性.
- 之前的碎片选方法受到可逆结合物的低亲和度的限制.
研究的目的:
- 开发一种实用且高效的方法来发现选择性共价配体.
- 克服与电友碎片相关的选择性挑战.
- 发现新型的共价探测器来挑战蛋白质目标.
主要方法:
- 一个993个成员的轻微电友碎片库的构建和表征.
- 开发一种高通量醇反应性试验,用于碎片的表征.
- 对10种含有囊蛋白的库进行选,然后进行高通量结晶学.
主要成果:
- 轻微的电友被证明是有选择性的,高度反应的碎片很少见.
- 选方法对大多数测试的蛋白质目标产生了结果.
- 对于OTUB2和NUDT7,这些没有先前已知的抑制剂的酶,迅速开发出强效和选择性的共价探针.
结论:
- 电片选是一种可行且有效的共价配体发现策略.
- 可以成功地使用温和的电友来实现目标选择性.
- 这种方法可以快速识别酶标的新型共价探针.
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