In silico investigation of interactions between human cannabinoid receptor-1 and its antagonists.

Cannabinoid receptor-1 (CB(1)) is widely expressed in the central nervous system and plays a vital role in regulating food intake and energy expenditure. CB(1) antagonists such as Rimonabant have been used in clinic to inhibit food intake, and therefore reduce body weight in obese animals and humans. To investigate the binding modes of CB(1) antagonists to the receptor, both receptor- and ligand-based methods were implemented in this study. At first, a pharmacophore model was generated based on 31 diverse CB(1) antagonists collected from literature. A test set validation and a simulated virtual screening evaluation were then performed to verify the reliability and discriminating ability of the pharmacophore. Meanwhile, the homology model of CB(1) receptor was constructed based on the crystal structure of human β (2) adrenergic receptor (β (2)-AR). Several classical antagonists were then docked into the optimized homology model with induced fit docking method. A hydrogen bond between the antagonists and Lys192 on the third transmembrane helix of the receptor was formed in the docking study, which has proven to be critical for receptor-ligand interaction by biological experiments. The structure obtained from induced fit docking was then confirmed to be a reliable model for molecular docking from the result of the simulated virtual screening. The consistency between the pharmacophore and the homology structure further proved the previous observation. The built receptor structure and antagonists' pharmacophore should be useful for the understanding of inhibitory mechanism and development of novel CB(1) antagonists.