Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV n 3, 16132 Genova, Italy.
Eur J Med Chem. 2011 Sep;46(9):4489-505. doi: 10.1016/j.ejmech.2011.07.023. Epub 2011 Jul 23.
CB2 receptor belongs to the large family of G-protein coupled receptors (GPCRs) controlling a wide variety of signal transduction. The recent crystallographic determination of human β2 adrenoreceptor and its high sequence similarity with human CB2 receptor (hCB2) prompted us to compute a theoretical model of hCB2 based also on β2 adrenoreceptor coordinates. This model has been employed to perform docking and molecular dynamic simulations on WIN-55,212-2 (CB2 agonist commonly used in binding experiments), in order to identify the putative CB2 receptor agonist binding site, followed by molecular docking studies on a series of indol-3-yl-tetramethylcyclopropyl ketone derivatives, a novel class of potent CB2 agonists. Successively, docking-based Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) studies were also performed. The CoMSIA model resulted to be the more predictive, showing r(ncv)(2) = 0.96, r(cv)(2) = 0.713, SEE = 0.193, F = 125.223, and r(2)(pred) = 0.78. The obtained 3D-QSAR models allowed us to derive more complete guidelines for the design of new analogues with improved potency so as to synthesize new indoles showing high CB2 affinity.
CB2 受体属于 G 蛋白偶联受体 (GPCRs) 大家族，可控制多种信号转导。最近人类β2 肾上腺素能受体的晶体结构测定及其与人 CB2 受体 (hCB2) 的高序列相似性促使我们根据β2 肾上腺素能受体坐标计算 hCB2 的理论模型。该模型已用于对 WIN-55,212-2 (常用于结合实验的 CB2 激动剂) 进行对接和分子动力学模拟，以确定潜在的 CB2 受体激动剂结合位点，然后对一系列吲哚-3-基-四甲基环丙基酮衍生物进行分子对接研究，这是一类新型强效 CB2 激动剂。随后，还进行了基于对接的比较分子场分析 (CoMFA) 和比较分子相似性指数分析 (CoMSIA) 研究。CoMSIA 模型更具预测性，r(ncv)(2) = 0.96、r(cv)(2) = 0.713、SEE = 0.193、F = 125.223 和 r(2)(pred) = 0.78。获得的 3D-QSAR 模型使我们能够得出更完整的设计新类似物的指导原则，以提高效力，从而合成具有高 CB2 亲和力的新型吲哚。
