Structure-based discovery of novel 4,5,6-trisubstituted pyrimidines as potent covalent Bruton’s tyrosine kinase inhibitors
Structure-based discovery of novel 4,5,6-trisubstituted pyrimidines as potent covalent Bruton’s tyrosine kinase inhibitors
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基于结构的新型 4,5,6-三取代嘧啶作为有效共价布鲁顿酪氨酸激酶抑制剂的发现
DOI：
10.1016/j.bmcl.2016.05.014
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发表时间：
2016
影响因子：
2.7
通讯作者：
Yisheng Lai
中科院分区：
文献类型：
--
作者：
Yi Zou;Jianhu Xiao;Zhengchao Tu;Yingyi Zhang;Kun Yao;Minghao Luo;Ke Ding;Yihua Zhang;Yisheng Lai
基于伊曲替尼的结构，采用开环策略，设计了一系列新型的4，5，6-三取代嘧啶类化合物作为有效的共价布鲁顿酪氨酸激酶（BTK）抑制剂。其中化合物I1表现出最强的抑制活性，IC 50值为0.07 μM。初步讨论了结构与活性的关系，并指出嘧啶C-4位的伯氨基是维持BTK活性的关键。此外，对3种BTK复合物进行了分子动力学模拟和结合自由能计算，确定了可能的结合模式，为进一步的结构修饰和优化提供了全面的指导。
A series of novel 4,5,6-trisubstituted pyrimidines were designed as potent covalent Bruton’s tyrosine kinase (BTK) inhibitors based on the structure of ibrutinib by using a ring-opening strategy. Among these derivatives, compoundI1exhibited the most potent inhibitory activity with an IC50value of 0.07 μM. The preliminary structure–activity relationship was discussed and the primary amino group at the C-4 position of pyrimidine was crucial for maintaining BTK activity. Furthermore, molecular dynamics simulations and binding free energy calculations were performed for three inhibitor-BTK complexes to determine the probable binding model, which provided a comprehensive guide for further structural modification and optimization.