The application of 3D-QSAR studies for novel cannabinoid ligands substituted at the C1' position of the alkyl side chain on the structural requirements for binding to cannabinoid receptors CB1 and CB2
The application of 3D-QSAR studies for novel cannabinoid ligands substituted at the C1' position of the alkyl side chain on the structural requirements for binding to cannabinoid receptors CB1 and CB2
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DOI：
10.1021/jm0610705
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发表时间：
2007-06-14
影响因子：
7.3
通讯作者：
Mavromoustakos, Thomas
中科院分区：
文献类型：
--
作者：
Durdagi, Serdar;Kapou, Agnes;Mavromoustakos, Thomas
采用比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）方法，对30个新的Delta（8）-四氢大麻酚和大麻二酚类似物进行了三维定量构效关系研究。使用分子建模技术和核磁共振光谱的结合，确定了训练集中最有效的大麻素（CB）配体的推定生物活性构象。以该构象异构体为模板，建立了CB 1和CB 2药效团模型。这些模型与实验结合数据拟合，并给出了较高的相关系数。CoMFA和CoMSIA方法的CB 1和CB 2模型的等高线图显示，空间效应主要决定结合亲和力。基于CB配体在CB 1和CB 2受体上的结合亲和力数据的CoMFA和CoMSIA分析使我们能够推断出可能的最佳结合位置。这些信息可用于设计具有增强活性和其他定制性质的新CB类似物。
A set of 30 novel Delta(8)-tetrahydrocannabinol and cannabidiol analogues were subjected to three-dimensional quantitative structure-activity relationship studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. Using a combination of molecular modeling techniques and NMR spectroscopy, the putative bioactive conformation of the most potent cannabinoid (CB) ligand in the training set was determined. This conformer was used as the template and CB1 and CB2 pharmacophore models were developed. These models were fitted with experimental binding data and gave high correlation coefficients. Contour maps of the CB1 and CB2 models of CoMFA and CoMSIA approaches show that steric effects dominantly determine the binding affinities. The CoMFA and CoMSIA analyses based on the binding affinity data of CB ligands at the CB1 and CB2 receptors allowed us to deduce the possible optimal binding positions. This information can be used for the design of new CB analogues with enhanced activity and other tailored properties.