Discovery of an SphK1 inhibitor: A hybrid approach involving a receptor–ligand-complex-based pharmacophore and docking-based virtual screening

Tiandi Ding, HaiJiao Chen, Yan Li, Ying Li, Y.. Zhi, Zhiqiang Qu, Qiang Sun, Qingqiang Yao, Bo Liu
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Abstract

Sphingosine kinase is a lipid kinase that catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate. Sphingosine-1-phosphate is a bioactive lipid that regulates biological processes. The overexpression of sphingosine kinases is related to a variety of pathophysiological conditions. For example, SphK1 has been shown to be highly expressed in various cancer cells including ovarian, cervical, colon, stomach, lung, and brain cancer. Inhibition of sphingosine kinases is a promising way to treat diseases such as cancer. Through computer-aided drug design, we have discovered a new SphK1 inhibitor named Amb30572637 (SAMS10). In this report, we describe the discovery process and biological characteristics. In biochemical experiments, SAMS10 shows a prominent inhibitory effect on SphK1, with an IC50 value of 9.8 μM. Subsequent MTT experiments show that SAMS10 has anticancer effects toward A549, SKVO3, A375, and LOVO cell lines and has essentially no cytotoxicity against the healthy cell L929. SAMS10 has significant inhibitory activity against the A549 and LOVO cell lines, with IC50 values of 14.64 and 14.48 μM, respectively. It belongs to a moderately active SphK1 inhibitor with lower anticancer activity than the control compound cisplatin, but the effect of SAMS10 toward SphK1 and its anticancer activity indicate that it is a promising lead compound for the development of effective SphK1 anticancer inhibitors.
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SphK1抑制剂的发现:基于受体-配体复合物的药效团和基于对接的虚拟筛选的混合方法
鞘氨醇激酶是一种脂质激酶,可催化鞘氨醇磷酸化为鞘氨醇-1-磷酸。鞘氨醇-1-磷酸是一种调节生物过程的生物活性脂质。鞘氨醇激酶的过度表达与多种病理生理条件有关。例如,SphK1已被证明在卵巢癌、宫颈癌、结肠癌、胃癌、肺癌和脑癌等多种癌细胞中高度表达。抑制鞘氨醇激酶是治疗癌症等疾病的一种很有前途的方法。通过计算机辅助药物设计,我们发现了一种新的SphK1抑制剂Amb30572637 (SAMS10)。在本报告中,我们描述了发现过程和生物学特性。在生化实验中,SAMS10对SphK1表现出明显的抑制作用,IC50值为9.8 μM。随后的MTT实验表明,SAMS10对A549、SKVO3、A375和LOVO细胞系具有抗癌作用,而对健康细胞L929基本没有细胞毒性。SAMS10对A549和LOVO细胞株具有显著的抑制活性,IC50值分别为14.64 μM和14.48 μM。它是一种中等活性的SphK1抑制剂,抗癌活性低于对照化合物顺铂,但SAMS10对SphK1的作用及其抗癌活性表明,它是开发有效的SphK1抗癌抑制剂的有希望的先导化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Chemical Research-s
Journal of Chemical Research-s 化学科学, 有机化学, 有机合成
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审稿时长
1 months
期刊介绍: The Journal of Chemical Research is a peer reviewed journal that publishes full-length review and research papers in all branches of experimental chemistry. The journal fills a niche by also publishing short papers, a format which favours particular types of work, e.g. the scope of new reagents or methodology, and the elucidation of the structure of novel compounds. Though welcome, short papers should not result in fragmentation of publication, they should describe a completed piece of work. The Journal is not intended as a vehicle for preliminary publications. The work must meet all the normal criteria for acceptance as regards scientific standards. Papers that contain extensive biological results or material relating to other areas of science may be diverted to more appropriate specialist journals. Areas of coverage include: Organic Chemistry; Inorganic Chemistry; Materials Chemistry; Crystallography; Computational Chemistry.
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