通过模块化"直接对生物学"查加速SARS-CoV-2主要蛋白酶抑制剂的发现.
Harry Wilders1,2,3, George Biggs2, Sam M Rowe1
1Chemical Biology, GSK, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
Angewandte Chemie (International ed. in English)
|December 4, 2024
概括
这项研究引入了一个直接对生物学 (D2B) 选平台,用于反应片段 (RF) 优化. 这种方法加速了对共价和可逆抑制剂的发现,以向SARS-CoV-2主要蛋白酶 (MPro) 为例.
科学领域:
- 药用化学 医学化学
- 药物发现 药物发现 药物发现
- 生物化学 生物化学
背景情况:
- 反应片段 (RF) 选对连接体发现是有效的,但优化通常是低吞吐量.
- 传统的优化需要大量的合成和净化,限制了效率.
研究的目的:
- 开发和验证一个高效的直接到生物 (D2B) 选平台,用于反应性碎片优化.
- 加速发现和优化SARS-CoV-2主要蛋白酶 (MPro) 抑制剂.
主要方法:
- 开发了一种D2B选平台,用于使用384井板合成向氨酸胺射频.
- 在没有化合物净化的情况下进行了直接的生物评估.
- 应用该平台以优化SARS-CoV-2抑制剂MPro.
主要成果:
- 成功优化了最初的射频击中强大的MPro抑制剂.
- 使用D2B查,证明了从共价抑制剂系列到可逆抑制剂系列的"切换".
- 实现了RFs对共价和非共价抑制剂候选者的加速优化.
结论:
- D2B平台显著提高了用于药物发现的射频优化的效率.
- 这种方法加速了对共价抑制剂候选者的开发,并促进了对非共价连接体的探索.
- D2B策略为优化活性片段成各种带类型提供了一个有希望的未来方向.
相关概念视频
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