Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No.826, Zhangheng Rd., Shanghai 201203, People's Republic of China.
State Key Lab of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, People's Republic of China.
Eur J Med Chem. 2014 Feb 12;73:1-7. doi: 10.1016/j.ejmech.2013.12.002. Epub 2013 Dec 14.
Sphingomyelin synthase (SMS), which catalyzes ceramide as one of the substrates to produce sphingomyelin, is a critical factor in the sphingolipid biosynthesis pathway. Recent studies indicated that SMS could serve as a novel potential drug target for the treatment of various metabolic diseases such as insulin resistance and atherosclerosis. However, very few small-molecule inhibitors of SMS are known. In this study, we performed structure-based virtual screening in combination with chemical synthesis and bioassay and discovered a class of small-molecule SMS inhibitors. The most potent compound exhibited an IC50 value lower than 20 μM in an in vitro enzymatic assay. To the best of our knowledge, this is the first time that small-molecule SMS inhibitors with potency close to the micromolar range are publicly revealed. The structure-activity relationship demonstrated by this class of compounds provides insights into the structural features that are essential for effective SMS inhibition.
鞘氨醇合酶（SMS）是鞘脂生物合成途径中的关键酶，它可以催化神经酰胺作为底物之一生成鞘磷脂。最近的研究表明，SMS 可以作为一种新型的潜在药物靶点，用于治疗各种代谢性疾病，如胰岛素抵抗和动脉粥样硬化。然而，目前已知的 SMS 小分子抑制剂非常少。在本研究中，我们采用基于结构的虚拟筛选结合化学合成和生物测定，发现了一类小分子 SMS 抑制剂。在体外酶促测定中，最有效的化合物表现出低于 20 μM 的 IC50 值。据我们所知，这是首次公开报道具有接近微摩尔效力的小分子 SMS 抑制剂。该类化合物的构效关系为有效 SMS 抑制所必需的结构特征提供了深入的了解。
