天然产物广泛用于治疗线粒体功能障碍相关疾病和癌症。姜黄素,一种著名的天然产品,可用于治疗癌症。人盐诱导激酶3(SIK3)是姜黄素的靶蛋白之一。然而,姜黄素与人SIK3之间的相互作用尚未得到详细研究。在这项研究中,我们使用同源性建模等计算工具研究了姜黄素与人SIK3之间相互作用的结合模型,分子对接,分子动力学模拟,和有约束力的自由能计算。SIK3与酮烯醇形式的姜黄素的开放活性环构象是最佳结合模型。I72、V80、A93、Y144、A145和L195残基对于姜黄素与人SIK3的结合起关键作用。姜黄素与人SIK3之间的相互作用也使用激酶测定进行了研究。此外,姜黄素表现出131nM的IC50(半最大抑制浓度)值,它对MCF-7和MDA-MB-23细胞系显示出9.62±0.33µM和72.37±0.37µM的显着抗增殖活性,分别。这项研究提供了有关姜黄素与人SIK3结合的详细信息,并可能有助于设计新型盐诱导型激酶抑制剂。
Natural products are widely used for treating mitochondrial dysfunction-related diseases and cancers. Curcumin, a well-known natural product, can be potentially used to treat cancer. Human salt-induced kinase 3 (SIK3) is one of the target proteins for curcumin. However, the interactions between curcumin and human SIK3 have not yet been investigated in detail. In this study, we studied the binding models for the interactions between curcumin and human SIK3 using computational tools such as homology modeling, molecular docking, molecular dynamics simulations, and binding free energy calculations. The open activity loop conformation of SIK3 with the ketoenol form of curcumin was the optimal binding model. The I72, V80, A93, Y144, A145, and L195 residues played a key role for curcumin binding with human SIK3. The interactions between curcumin and human SIK3 were also investigated using the kinase assay. Moreover, curcumin exhibited an IC50 (half-maximal inhibitory concentration) value of 131 nM, and it showed significant antiproliferative activities of 9.62 ± 0.33 µM and 72.37 ± 0.37 µM against the MCF-7 and MDA-MB-23 cell lines, respectively. This study provides detailed information on the binding of curcumin with human SIK3 and may facilitate the design of novel salt-inducible kinases inhibitors.