Molecular principle of the cyclin-dependent kinase selectivity of 4-(thiazol-5-yl)-2-(phenylamino) pyrimidine-5-carbonitrile derivatives revealed by molecular modeling studies
Molecular principle of the cyclin-dependent kinase selectivity of 4-(thiazol-5-yl)-2-(phenylamino) pyrimidine-5-carbonitrile derivatives revealed by molecular modeling studies
复制标题
分子模型研究揭示4-(噻唑-5-基)-2-(苯氨基)嘧啶-5-甲腈衍生物的细胞周期蛋白依赖性激酶选择性的分子原理
DOI：
10.1039/c5cp05622e
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发表时间：
2016-01-21
影响因子：
3.3
通讯作者：
Hou, Tingjun
中科院分区：
文献类型：
--
作者：
Kong, Xiaotian;Sun, Huiyong;Hou, Tingjun
由于细胞周期蛋白依赖性激酶(CDK)结合口袋的高度序列同源性，设计针对特定CDK成员的高选择性抑制剂仍然是一个巨大的挑战。4-(噻唑-5-基)-2(苯氨基)嘧啶类化合物是CDKs的有效抑制剂，其中最有希望的12u与CDK9具有较高的结合亲和力，而与其他同源激酶如CDK2的结合亲和力减弱。在这项研究中，为了解释CDK9对CDK2的结合偏好原理，并探索可能有助于设计选择性CDK9抑制剂的关键信息，基于传统的分子动力学(MD)模拟和改进的抽样模拟(伞形抽样和转向MD模拟)对两个典型的衍生物(12u和4)进行了MM/GBSA计算。计算结果表明，12U与CDK9结合的特异性主要受G环构象变化和van der Waals相互作用的影响。此外，增强的采样模拟揭示了抑制剂12u和4从CDK9和CDK2结合口袋解离时不同的反应坐标和瞬时相互作用。本研究获得的物理原理可能有助于发现和合理设计新型的、特异的CDK9抑制剂。
Due to the high sequence identity of the binding pockets of cyclin-dependent kinases (CDKs), designing highly selective inhibitors towards a specific CDK member remains a big challenge. 4-(thiazol-5-yl)-2(phenylamino) pyrimidine derivatives are effective inhibitors of CDKs, among which the most promising inhibitor 12u demonstrates high binding affinity to CDK9 and attenuated binding affinity to other homologous kinases, such as CDK2. In this study, in order to rationalize the principle of the binding preference towards CDK9 over CDK2 and to explore crucial information that may aid the design of selective CDK9 inhibitors, MM/GBSA calculations based on conventional molecular dynamics (MD) simulations and enhanced sampling simulations (umbrella sampling and steered MD simulations) were carried out on two representative derivatives (12u and 4). The calculation results show that the binding specificity of 12u to CDK9 is primarily controlled by conformational change of the G-loop and variation of the van der Waals interactions. Furthermore, the enhanced sampling simulations revealed the different reaction coordinates and transient interactions of inhibitors 12u and 4 as they dissociate from the binding pockets of CDK9 and CDK2. The physical principles obtained from this study may facilitate the discovery and rational design of novel and specific inhibitors of CDK9.