Shi Mingsong, Wang Lun, Li Penghui, Liu Jiang, Chen Lijuan, Xu Dingguo
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
MOE Key Laboratory of Green Chemistry and Technology, College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, China.
ACS Omega. 2021 Apr 15;6(16):11025-11038. doi: 10.1021/acsomega.1c00947. eCollection 2021 Apr 27.
Salt-inducible kinases (SIKs) are calcium/calmodulin-dependent protein kinase (CAMK)-like (CAMKL) family members implicated in insulin signal transduction, metabolic regulation, inflammatory response, and other processes. Here, we focused on SIK2, which is a target of the Food and Drug Administration (FDA)-approved pan inhibitor -(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (dasatinib), and constructed four representative SIK2 structures by homology modeling. We investigated the interactions between dasatinib and SIK2 via molecular docking, molecular dynamics simulation, and binding free energy calculation and found that dasatinib showed strong binding affinity for SIK2. Binding free energy calculations suggested that the modification of various dasatinib regions may provide useful information for drug design and to guide the discovery of novel dasatinib-based SIK2 inhibitors.
盐诱导激酶（SIKs）是钙/钙调蛋白依赖性蛋白激酶（CAMK）样（CAMKL）家族成员，参与胰岛素信号转导、代谢调节、炎症反应和其他过程。在此，我们聚焦于SIK2，它是美国食品药品监督管理局（FDA）批准的泛抑制剂（2-氯-6-甲基苯基）-2-（6-（4-（2-羟乙基）哌嗪-1-基）-2-甲基嘧啶-4-基氨基）噻唑-5-甲酰胺（达沙替尼）的作用靶点，并通过同源建模构建了四种代表性的SIK2结构。我们通过分子对接、分子动力学模拟和结合自由能计算研究了达沙替尼与SIK2之间的相互作用，发现达沙替尼对SIK2表现出很强的结合亲和力。结合自由能计算表明，对达沙替尼各个区域的修饰可能为药物设计提供有用信息，并指导发现新型基于达沙替尼的SIK2抑制剂。
