Department of Medicinal Chemistry and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
Department of Anesthesiology, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, China.
Chem Biol Drug Des. 2018 Sep;92(3):1699-1707. doi: 10.1111/cbdd.13337. Epub 2018 Jun 19.
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 Lys192 in CB1 was engaged in indirect interactions with ligands to keep inactive-state CB1 stable by forming the salt bridge with Asp176 . 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.
人类大麻素 G 蛋白偶联受体 1（CB1）在中枢神经系统中高度表达。CB1 选择性拮抗剂在一系列疾病中显示出治疗潜力，例如与肥胖相关的代谢紊乱、血脂异常、药物滥用和 2 型糖尿病。利莫那班（SR141716A）、MJ08 和 MJ15 是选择性 CB1 拮抗剂，与 CB2 的选择性超过 1000 倍，尽管 CB1 和 CB2 之间有 42%的序列同一性。同源建模、自动分子对接和分子动力学模拟的整合用于研究这些选择性反向激动剂/拮抗剂与 CB1 和 CB2 的结合模式及其选择性。我们的分析表明，配体与 CB1 疏水口袋之间的疏水相互作用是主要的结合亲和力。此外，与之前报道的相反，CB1 中的 Lys192 参与间接相互作用，通过与 Asp176 形成盐桥，使处于非活性状态的 CB1 稳定，从而保持其稳定。最后，我们的分析表明，这些拮抗剂的选择性来自于 CB1 和 CB2 结合口袋的几何形状的差异。本研究可以为这些受体的未来实验工作提供指导，并对设计针对 CB1 或 CB2 受体的功能选择性药物具有指导意义。
