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.
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Eur J Med Chem. 2023 Apr 5;252:115271. doi: 10.1016/j.ejmech.2023.115271. Epub 2023 Mar 11.
Lysophosphatidylserine (LysoPS) is an endogenous pan-agonist of three G-protein coupled receptors (GPCRs): LPS/GPR34, LPS/P2Y, and LPS/GPR174, and we previously reported a series of LysoPS-based agonists of these receptors. Interestingly, we found that LPS agonist activity was very sensitive to structural change at the hydrophobic fatty acid moiety, whereas LPS agonist activity was not. Here, to probe the molecular basis of LPS agonist binding, we developed a new class of hydrophobic fatty acid surrogates having a biphenyl-ether scaffold. The LPS agonist activity of these compounds proved sensitive to molecular modification of the hydrophobic skeleton. Thus, we next constructed an LPS model by homology modeling and docking/molecular dynamics (MD) simulation, and validated it by means of SAR studies together with point mutations of selected receptor amino-acid residues. The putative ligand-binding site of LPS is Γ-shaped, with a hydrophilic site horizontally embedded in the receptor transmembrane helix bundles and a perpendicular hydrophobic groove adjoining transmembrane domains 4 and 5 that is open to the membrane bilayer. The binding poses of LPS agonists to this site are consistent with easy incorporation of various kinds of fatty acid surrogates. Structural development based on this model afforded a series of potent and selective LPS full agonists, which showed enhanced in vitro actin stress fiber formation effect.
溶血磷脂酰丝氨酸（LysoPS）是三种 G 蛋白偶联受体（GPCR）的内源性全激动剂：LPS/GPR34、LPS/P2Y 和 LPS/GPR174，我们之前报道了一系列这些受体的 LysoPS 基激动剂。有趣的是，我们发现 LPS 激动剂活性对疏水性脂肪酸部分的结构变化非常敏感，而 LPS 激动剂活性则不是。在这里，为了探究 LPS 激动剂结合的分子基础，我们开发了一类具有联苯醚骨架的新型疏水性脂肪酸替代物。这些化合物的 LPS 激动剂活性被证明对疏水性骨架的分子修饰很敏感。因此，我们接下来通过同源建模和对接/分子动力学（MD）模拟构建了一个 LPS 模型，并通过 SAR 研究以及对选定受体氨基酸残基的点突变对其进行了验证。LPS 的假定配体结合位点呈 Γ 形，水平嵌入受体跨膜螺旋束中的亲水位点和垂直疏水性凹槽，该凹槽毗邻跨膜域 4 和 5，通向膜双层。LPS 激动剂与该位点的结合构象与各种脂肪酸替代物的易掺入一致。基于该模型的结构开发提供了一系列强效和选择性的 LPS 完全激动剂，它们显示出增强的体外肌动蛋白应力纤维形成效应。
