对共价和性蛋白激酶抑制剂的系统分析.
Elena Xerxa1, Oliver Laufkötter1, Jürgen Bajorath1
1LIMES Program Unit Chemical Biology and Medicinal Chemistry, Department of Life Science Informatics, B-IT, Rheinische Friedrich-Wilhelms-Universität, Friedrich-Hirzebruch-Allee 5/6, D-53115 Bonn, Germany.
Molecules (Basel, Switzerland)
|August 12, 2023
概括
性蛋白激酶抑制剂 (CPKIs) 显示出强度增加,特别是在特定的弹头,但不一定是更广泛的活动. 新的全性PKI (APKI) 也被确定用于基于结构的药物设计.
科学领域:
- 药用化学 医学化学
- 药理学 药理学是指药理学的学科.
- 结构生物学 结构生物学
背景情况:
- 蛋白质激酶抑制剂 (PKIs) 在药物发现中至关重要,人们越来越关注全性 (APKIs) 和共性 (CPKIs) 类型,以提高选择性和功效.
- 共价PKI (CPKI) 提供了潜在的优势,如高强度和延长的停留时间,推动了新的研究兴趣.
研究的目的:
- 系统地分析使用精选活动数据使用各种弹头的CPKIs的效力和乱交性.
- 为了确定基于结构的药物设计的新型全性PKI (APKI).
主要方法:
- 对具有不同反应弹头的CPKI进行公共领域活动数据的系统搜索和分析.
- 调查CPKI功效和多PK活性 (性交).
- 通过分析蛋白激酶-PKI复合体的X射线结构来识别新的APKI.
主要成果:
- 在七个CPKI弹头中的五个显示出与非共价类型相比,至少100倍的显著中位强度增加.
- 只有三个弹头显示CPKIs的中位强度明显高于非共价PKI.
- 与非共价PKI相比,对CPKIs没有观察到乱交的一般增加.
- 在X射线结构中发现了29种新的APKI,其中包括5种蛋白质激酶中的13种共价APKI.
结论:
- 在没有普遍增加非目标活动的情况下,CPKI可以提供显著的功率增长,特别是在特定的弹头上.
- 识别新的APKI,包括共价变异,为选择性激酶抑制剂的基于结构的设计提供了机会.
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