通过共价片段探测蛋白质激酶的囊蛋白
Guiqun Wang1,2,3, Nico J Seidler4, Sandra Röhm1,2
1Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 9, D-60438, Frankfurt am Main, Germany.
Angewandte Chemie (International ed. in English)
|December 24, 2024
概括
研究人员开发了一种使用共价片段抑制剂来向蛋白质激酶中的特定囊蛋白的可通用方法,使得药物开发中选择性抑制剂的发现成为可能.
科学领域:
- 生物化学 生物化学
- 化学生物学 化学生物学
- 药物发现 药物发现 药物发现
背景情况:
- 蛋白质激酶是关键的药物标,但对500多种人类激酶的选择性抑制剂的开发仍然具有挑战性.
- 协同抑制剂通过向特定的蛋白质氨酸,比非协同抑制剂类型提供更强的选择性.
- 之前的共价碎片选侧重于单个激酶,使许多可向的半氨酸未被解决.
研究的目的:
- 建立一种可通用的方法,使用共价片段在蛋白质激酶中准ATP位的囊蛋白.
- 开发和选针对多种类型的激酶的聚焦共价片段库.
- 识别具有高强度和选择性潜力的新型共价抑制剂.
主要方法:
- 开发一个以激酶为重点的共价片段库.
- 使用LC/MS和差异扫描度法 (DSF) 对47个激酶进行系统查,对60个活跃位点附近的类蛋白进行查.
- 使用互补的生物物理和结构技术进行击中验证.
主要成果:
- 成功识别了ovalent片段的命中,这些命中针对蛋白质激酶中以前未被解决的囊蛋白.
- 通过晶体结构分析,阐明独特的激酶共价抑制剂结合模式.
- 发现异形特异性共价抑制剂,具有有前途的特性,可用于进一步开发.
结论:
- 开发的方法可用于在基因组中准ATP站点氨酸.
- 这项工作扩大了蛋白质激酶中的可药物化氨酸景观.
- 已识别的共价抑制剂作为开发高度选择性酶向治疗的有价值的起点.
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