评估氨酸和氨酸的反应性,以设计向的共价激酶抑制剂
Ruibin Liu1, Zhi Yue1, Cheng-Chieh Tsai1
1Department of Pharmaceutical Sciences , School of Pharmacy, University of Maryland , Baltimore , Maryland 21201 , United States.
Journal of the American Chemical Society
|April 5, 2019
概括
素向的共价抑制剂提供了一种超出囊基药物的新策略, 解决药物耐药性等局限性. 这项研究确定了激酶中的反应性溶酶,加速了理性共价抑制剂的发现.
科学领域:
- 生物化学
- 医学化学
- 计算生物学
背景情况:
- 有针对性的共价抑制剂设计越来越重要.
- 向囊是常见的,但由于稀少性和耐药性而受到限制.
- 素向探测器激发了对素反应性的探索.
研究的目的:
- 研究人类激酶中核性 (反应性) 催化酶的流行情况.
- 开发一种新的策略来设计有选择性的氨酸向的共价激酶抑制剂.
- 评估一种新的pKa预测工具用于识别反应残留物的潜力.
主要方法:
- 使用基于连续恒定的pH分子动态的pKa预测工具.
- 分析了人类基因组的已发表的晶体结构.
- 在特定的激酶结构 (DFG-out/αC-out) 中,回顾性和前性预测 lysine 反应性.
主要成果:
- 预测催化溶酶在特定的激酶结构中具有核友性.
- 在各种激酶位点中发现了其他反应性 lysines 和 cysteines.
- 氨酸和氨酸可以在生理pH中存在中性和充电状态,这挑战了当前的计算假设.
结论:
- 通过修改II型可逆抑制剂来设计选择性氨酸向共价激酶抑制剂的新策略.
- 开发的pKa预测工具可以加速对共价抑制剂的合理发现.
- 对 lysine 和 cysteine 质子化状态的发现可能会改变计算激酶研究.
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