Sayama Misa, Inoue Asuka, Nakamura Sho, Jung Sejin, Ikubo Masaya, Otani Yuko, Uwamizu Akiharu, Kishi Takayuki, Makide Kumiko, Aoki Junken, Hirokawa Takatsugu, Ohwada Tomohiko
Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
J Med Chem. 2017 Jul 27;60(14):6384-6399. doi: 10.1021/acs.jmedchem.7b00693. Epub 2017 Jul 17.
The ligands of certain G-protein-coupled receptors (GPCRs) have been identified as endogenous lipids, such as lysophosphatidylserine (LysoPS). Here, we analyzed the molecular basis of the structure-activity relationship of ligands of GPR34, one of the LysoPS receptor subtypes, focusing on recognition of the long-chain fatty acid moiety by the hydrophobic pocket. By introducing benzene ring(s) into the fatty acid moiety of 2-deoxy-LysoPS, we explored the binding site's preference for the hydrophobic shape. A tribenzene-containing fatty acid surrogate with modifications of the terminal aromatic moiety showed potent agonistic activity toward GPR34. Computational docking of these derivatives with a homology modeling/molecular dynamics-based virtual binding site of GPR34 indicated that a kink in the benzene-based lipid surrogates matches the L-shaped hydrophobic pocket of GPR34. A tetrabenzene-based lipid analogue bearing a bulky tert-butyl group at the 4-position of the terminal benzene ring exhibited potent GPR34 agonistic activity, validating the present hydrophobic binding pocket model.
某些G蛋白偶联受体（GPCR）的配体已被确定为内源性脂质，如溶血磷脂酰丝氨酸（LysoPS）。在此，我们分析了LysoPS受体亚型之一GPR34配体的构效关系的分子基础，重点关注疏水口袋对长链脂肪酸部分的识别。通过将苯环引入2-脱氧-LysoPS的脂肪酸部分，我们探究了结合位点对疏水形状的偏好。一种对末端芳香部分进行修饰的含三苯脂肪酸类似物对GPR34表现出强效激动活性。这些衍生物与基于同源建模/分子动力学的GPR34虚拟结合位点的计算对接表明，基于苯的脂质类似物中的一个扭结与GPR34的L形疏水口袋相匹配。一种在末端苯环的4位带有庞大叔丁基的基于四苯的脂质类似物表现出强效GPR34激动活性，验证了当前的疏水结合口袋模型。
