Structure-Activity Relationships of GPR120 Agonists Based on a Docking Simulation
Structure-Activity Relationships of GPR120 Agonists Based on a Docking Simulation
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DOI：
10.1124/mol.110.066324
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发表时间：
2010-11-01
影响因子：
3.6
通讯作者：
Tsujimoto, Gozoh
中科院分区：
文献类型：
--
作者：
Sun, Qi;Hirasawa, Akira;Tsujimoto, Gozoh
GPR120是一种G蛋白偶联受体，主要在肠道和脂肪组织中表达，参与调节游离脂肪酸刺激的胰高血糖素样肽-1(GLP-1)的分泌。为了开发GPR120特异性激动剂，合成了一系列来源于过氧化体增殖物激活受体γ激动剂的化合物(NCG化合物)，并探索了它们作为GPR120激动剂的构效关系。为了检验这些新合成的NCG化合物和已被证明具有GPR120激动剂活性的化合物(格列叶酸和MEDICA16)的激动活性，我们在GPR120同源模型中进行了对接模拟，该模型是基于牛视紫质晶体结构的光激活模型而开发的。我们计算了化合物与GPR120模型之间的氢键能。这些能量与化合物的GPR120激活性有很好的相关性(R2=0.73)。NCG21是计算氢键能最低的NCG化合物，在克隆的GPR120系统中显示出最强的细胞外信号调节激酶(ERK)激活。此外，NCG21还能有效地激活内源性表达GPR120的小鼠肠内分泌STC-1细胞ERK、细胞内钙反应和GLP-1分泌。此外，小鼠结肠内注射NCG21可引起血浆GLP-1水平升高。综上所述，我们目前的研究表明，使用GPR120同源模型的对接模拟可能有助于预测化合物的激动活性。
GPR120 is a G protein-coupled receptor expressed preferentially in the intestinal tract and adipose tissue, that has been implicated in mediating free fatty acid-stimulated glucagon-like peptide-1 (GLP-1) secretion. To develop GPR120-specific agonists, a series of compounds (denoted as NCG compounds) derived from a peroxisome proliferator-activated receptor gamma agonist were synthesized, and their structure-activity relationships as GPR120 agonists were explored. To examine the agonistic activities of these newly synthesized NCG compounds, and of compounds already shown to have GPR120 agonistic activity (grifolic acid and MEDICA16), we conducted docking simulation in a GPR120 homology model that was developed on the basis of a photoactivated model derived from the crystal structure of bovine rhodopsin. We calculated the hydrogen bonding energies between the compounds and the GPR120 model. These energies correlated well with the GPR120 agonistic activity of the compounds (R-2 = 0.73). NCG21, the NCG compound with the lowest calculated hydrogen bonding energy, showed the most potent extracellular signal-regulated kinase (ERK) activation in a cloned GPR120 system. Furthermore, NCG21 potently activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express GPR120 endogenously. Moreover, administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Taken together, our present study showed that a docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds.