Computational investigation on the binding modes of Rimonabant analogs with CB 1 and CB 2

The human cannabinoid G‐protein‐coupled receptor 1 ( CB 1) is highly expressed in central nervous system. CB 1‐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 ( SR 141716A), MJ 08, and MJ 15 are selective CB 1 antagonists with selectivity >1,000‐folds over CB 2 despite 42% sequence identity between CB 1 and CB 2. 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 CB 1 and CB 2 and their selectivity. Our analyses showed that the hydrophobic interactions between ligands and hydrophobic pockets of CB 1 account for the main binding affinity. In addition, instead of interacting with ligands directly as previously reported, the Lys192 3.28 in CB 1 was engaged in indirect interactions with ligands to keep inactive‐state CB 1 stable by forming the salt bridge with Asp176 2.63 . Lastly, our analyses indicated that the selectivity of these antagonists came from the difference in geometry shapes of binding pockets of CB 1 and CB 2. The present study could guide future experimental works on these receptors and has the guiding significance for the design of functionally selective drugs targeting CB 1 or CB 2 receptors.