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Computational investigation on the binding modes of Rimonabant analogs with CB1 and CB2
Chemical Biology & Drug Design ( IF 3 ) Pub Date : 2018-06-19 , DOI: 10.1111/cbdd.13337
Cheng Liu 1 , Congmin Yuan 1 , Pinwen Wu 2 , Chen Zhu 1 , Hao Fang 2, 3 , Lili Wang 4 , Wei Fu 1, 2
Affiliation  

The human cannabinoid G‐protein‐coupled receptor 1 (CB1) is highly expressed in central nervous system. CB1‐selective antagonists show therapeutic promise in a wide range of disorders, such as obesity‐related metabolic disorders, dyslipidemia, drug abuse, and type 2 diabetes. Rimonabant (SR141716A), MJ08, and MJ15 are selective CB1 antagonists with selectivity >1,000‐folds over CB2 despite 42% sequence identity between CB1 and CB2. The integration of homology modeling, automated molecular docking, and molecular dynamics simulation were used to investigate the binding modes of these selective inverse agonists/antagonists with CB1 and CB2 and their selectivity. Our analyses showed that the hydrophobic interactions between ligands and hydrophobic pockets of CB1 account for the main binding affinity. In addition, instead of interacting with ligands directly as previously reported, the Lys1923.28 in CB1 was engaged in indirect interactions with ligands to keep inactive‐state CB1 stable by forming the salt bridge with Asp1762.63. Lastly, our analyses indicated that the selectivity of these antagonists came from the difference in geometry shapes of binding pockets of CB1 and CB2. The present study could guide future experimental works on these receptors and has the guiding significance for the design of functionally selective drugs targeting CB1 or CB2 receptors.

中文翻译:

利莫那班类似物与CB1和CB2结合模式的计算研究

人大麻素G蛋白偶联受体1(CB1)在中枢神经系统中高度表达。CB1选择性拮抗剂在多种疾病中显示出治疗前景,例如与肥胖相关的代谢性疾病,血脂异常,药物滥用和2型糖尿病。Rimonabant(SR141716A),MJ08和MJ15是选择性CB1拮抗剂,尽管CB1和CB2之间具有42%的序列同一性,但其选择性是CB2的1000倍以上。同源性建模,自动分子对接和分子动力学模拟的集成用于研究这些选择性的反向激动剂/拮抗剂与CB1和CB2的结合模式及其选择性。我们的分析表明,配体和CB1的疏水口袋之间的疏水相互作用是主要的结合亲和力。此外,CB1中的3.28与配体间接相互作用,可通过与Asp176 2.63形成盐桥来保持非活性状态CB1稳定。最后,我们的分析表明,这些拮抗剂的选择性来自CB1和CB2结合口袋的几何形状的差异。本研究可以指导这些受体的未来实验工作,对设计针对CB1或CB2受体的功能选择性药物具有指导意义。
更新日期:2018-06-19
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