Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor.
Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor.
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CB1 受体新型反向激动剂的计算预测和生化分析。
DOI：
10.1021/acs.jcim.5b00581
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发表时间：
2016
影响因子：
5.6
通讯作者：
Abrol,Ravinder
中科院分区：
文献类型：
--
作者：
Scott,CaitlinE;Ahn,KwangH;Graf,StevenT;Goddard3rd,WilliamA;Kendall,DebraA;Abrol,Ravinder
人大麻素 1 型 (CB1) G 蛋白偶联受体是肥胖症的潜在治疗靶点。先前预测和实验验证的 CB1 无配体构象集合 [Scott, C. E. 等人。蛋白质科学。 2013, 22, 101−113; Ahn，K.H. 等人。此处使用蛋白质 2013, 81, 1304–1317] 预测已知 CB1 选择性反向激动剂（包括利莫那班及其七种已知衍生物）的结合位点。该结合口袋与之前发表的模型显着不同，可通过利用潜在的新相互作用来识别 16 种有望成为 CB1 反向激动剂的新型化合物。我们通过实验证明其中两种化合物表现出反向激动剂特性，包括抑制基础和激动剂诱导的 G 蛋白偶联活性，以及增强 CB1 细胞表面定位水平。这证明了使用 CB1 受体结构整体的预测结合位点来设计新的 CB1 反向激动剂的效用。
Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity. The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 [Scott, C. E. et al. Protein Sci. 2013, 22, 101−113; Ahn, K. H. et al. Proteins 2013, 81, 1304–1317] are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives. This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions. We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization. This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists.