Structure-inspired design of a sphingolipid mimic sphingosine-1-phosphate receptor agonist from a naturally occurring sphingomyelin synthase inhibitor
Structure-inspired design of a sphingolipid mimic sphingosine-1-phosphate receptor agonist from a naturally occurring sphingomyelin synthase inhibitor
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DOI：
10.1039/c8cc05595e
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发表时间：
2018-11-21
影响因子：
4.9
通讯作者：
Monde, Kenji
中科院分区：
文献类型：
--
作者：
Swamy, Mahadeva M. M.;Murai, Yuta;Monde, Kenji
从植物提取物库中获得的作为鞘磷脂合酶抑制剂的银杏酸启发了鞘脂模拟物的概念。银杏酸衍生的N-酰基苯胺和银杏酸2-磷酸（GA 2 P）在结构和功能上分别模拟神经酰胺和1-磷酸鞘氨醇（S1 P）。GA 2 P诱导的ERK磷酸化和S1 P受体1（S1 P（1））的内化表明了有效的激动剂活性。对接研究表明，GA 2 P采用与结合配体ML 5相似的结合构象，ML 5是S1 P的强拮抗剂（1）。
Ginkgolic acid obtained as a sphingomyelin synthase inhibitor from a plant extract library inspired the concept of sphingolipid mimics. Ginkgolic acid-derived N-acyl anilines and ginkgolic acid 2-phosphate (GA2P) respectively mimic ceramide and sphingosine 1-phosphate (S1P) in structure and function. The GA2P-induced phosphorylation of ERK and internalization of S1P receptor 1 (S1P(1)) indicated potent agonist activity. Docking studies revealed that GA2P adopts a similar binding conformation to the bound ligand ML5, which is a strong antagonist of S1P(1).