通过X射线结晶学碎片查,在Pin1上发现可用药物的热点
Qingjie Xiao1, Jianchao Tang1, Huangliang Shu2
1National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, People's Republic of China.
European journal of medicinal chemistry
|August 13, 2025
概括
碎片查发现了抑制Pin1的新方法,Pin1是癌症中的关键蛋白质. 这项研究扩大了开发向抗癌药物的潜力,通过揭示新的结合部位和片段化学型.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药用化学 医学化学
背景情况:
- Pin1是细胞循环调节和信号转导中的关键酶,与瘤发生有关.
- 在各种癌症中Pin1的过度表达使其成为一个有前途的治疗点.
- 皮恩1的浅粘接表面给传统药物设计带来了挑战.
研究的目的:
- 通过使用基于结构的碎片选来克服设计挑战.
- 为了识别用于Pin1抑制的新型可用药物的结合口袋和碎片支架.
- 引导选择性和有效的Pin1抑制剂的开发.
主要方法:
- 一个策划的图书馆的基于X射线晶体学的碎片选.
- 识别和分析大约50个Pin1片段复杂结构.
- 酶抑制测定和质谱测试用于验证.
主要成果:
- 发现可使用药物的结合热点,包括催化中心 (网站1) 和邻近地区 (网站2).
- 标识在多个地点展现合作结合的碎片.
- 确认针对Cys113.3的反应碎片的共价结合模式.
- 在溶液中基于片段抑制Pin1活性的验证.
结论:
- 功能性结合口袋的系统映射扩大了Pin1.1的可用药物景观.
- 确定了用于抑制剂设计的关键结构特征和碎片化学型.
- 为开发用于癌症治疗的新型,选择性和多功能Pin1抑制剂提供了基础.
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