Evaluation of ellagic acid as an inhibitor of sphingosine kinase 1: A targeted approach towards anticancer therapy
Evaluation of ellagic acid as an inhibitor of sphingosine kinase 1: A targeted approach towards anticancer therapy
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DOI：
10.1016/j.biopha.2019.109245
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发表时间：
2019-10-01
影响因子：
7.5
通讯作者：
Hassan, Md Imtaiyaz
中科院分区：
文献类型：
--
作者：
Gupta, Preeti;Mohammad, Taj;Hassan, Md Imtaiyaz
鞘氨醇激酶1（SphK 1）是鞘脂代谢的中心酶之一，其高表达水平被推测与癌症和其它炎性疾病相关。使用虚拟筛选方法和体外研究，我们已经确定了鞣花酸（FA），一种膳食多酚，作为SphK 1的有效抑制剂。分子对接研究表明EA与SphK 1具有很强的结合亲和力。荧光结合和等温滴定量热法（ITC）的测量也表明了可观的结合亲和力。激酶抑制试验显示EA对SphK 1有很好的抑制作用（IC_（50）= 0.74 ± 0.06 μ M）。细胞活力研究指向EA对肺癌细胞系（A549）的抗增殖作用，而不影响人胚肾细胞（HEK 293）。通过对SphK 1-EA复合物的对接分析，揭示了EA的结合和抑制机制。EA结合到SphK 1，并与ATP结合口袋的催化重要残基形成几种相互作用。在100 ns的分子动力学模拟研究中SphK 1-EA复合物的结构稳定性和动力学分析表明，EA与SphK 1形成稳定的复合物，而不诱导任何显着的构象转变。总之，我们的研究表明，EA可以作为一种化学原型，开发针对SphK 1相关病理的有效治疗方法。
Sphingosine kinase 1 (SphK1) is one of the central enzymes of sphingolipid metabolism whose high expression level is presumed to be correlated with cancer and other inflammatory diseases. Using a virtual screening approach and in vitro studies, we have identified the ellagic acid (FA), a dietary polyphenol, as a potent inhibitor of SphK1. Molecular docking study has suggested a strong binding affinity of EA to the SphK1. Fluorescence binding and isothermal titration calorimetry (ITC) measurements has also indicated an appreciable binding affinity. Kinase inhibition assay revealed an excellent inhibitory action of EA towards SphK1 (IC50 = 0.74 +/- 0.06 mu M). Cell viability studies point towards the antiproliferative effects of EA on lung cancer cell line (A549) without affecting human embryonic kidney cells (HEK293). Binding and inhibition mechanism of EA was unveiled by docking analysis of SphK1-EA complex. EA binds to the SphK1 and forms several interactions with catalytically important residues of ATP-binding pocket. Structural stability and dynamics analysis of SphK1-EA complex during 100 ns molecular dynamic simulation studies suggested that EA forms a stable complex with SphK1 without inducing any significant conformational shift. Taken together, our study suggests that EA can be utilized as a chemical prototype to develop potent therapeutics targeting SphK1-associated pathologies.