Li Ya-Li, Qi Xiang-Yu, Jiang Hui, Deng Xiao-Dong, Dong Yan-Ping, Ding Ting-Bo, Zhou Lu, Men Peng, Chu Yong, Wang Ren-Xiao, Jiang Xian-Cheng, Ye De-Yong
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826, Zhangheng Rd., Shanghai 201203, China.
State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
Bioorg Med Chem. 2015 Sep 15;23(18):6173-84. doi: 10.1016/j.bmc.2015.07.060. Epub 2015 Jul 30.
Sphingomyelin synthase (SMS) has been proved to be a potential drug target for the treatment of atherosclerosis. However, few SMS inhibitors have been reported. In this paper, structure-based virtual screening was performed on hSMS1. SAPA 1a was discovered as a novel SMS1 inhibitor with an IC50 value of 5.2 μM in enzymatic assay. A series of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) were synthesized and their biological activities toward SMS1 were evaluated. Among them, SAPA 1j was found to be the most potent SMS1 inhibitor with an IC50 value of 2.1 μM in in vitro assay. The molecular docking studies suggested the interaction modes of SMS1 inhibitors and PC with the active site of SMS1. Site-directed mutagenesis validated the involvement of residues Arg342 and Tyr338 in enzymatic sphingomyelin production. The discovery of SAPA derivatives as a novel class of SMS1 inhibitors would advance the development of more effective SMS1 inhibitors.
鞘磷脂合酶（SMS）已被证明是治疗动脉粥样硬化的潜在药物靶点。然而，报道的SMS抑制剂很少。本文对人源SMS1（hSMS1）进行了基于结构的虚拟筛选。发现SAPA 1a是一种新型的SMS1抑制剂，在酶活性测定中IC50值为5.2 μM。合成了一系列2-(4-(N-苯乙基氨磺酰基)苯氧基)乙酰胺（SAPAs），并评估了它们对SMS1的生物活性。其中，SAPA 1j被发现是最有效的SMS1抑制剂，在体外测定中IC50值为2.1 μM。分子对接研究表明了SMS1抑制剂和磷脂酰胆碱（PC）与SMS1活性位点的相互作用模式。定点诱变验证了精氨酸342（Arg342）和酪氨酸338（Tyr338）残基参与了鞘磷脂的酶促生成。作为一类新型SMS1抑制剂的SAPA衍生物的发现将推动更有效的SMS1抑制剂的开发。
