Molecular docking of danuglipron uncovers potential crossovers between GLP-1R and the endocannabinoid system.

The targeting of the G-protein coupled receptor (GPCRs) glucagon-like-peptide-1-receptor (GLP-1R) by weight loss medications has become extremely prevalent due to the effectiveness of a class of GLP-1R agonists. Also, interest in cannabinoids, such as delta-9-tetrahydrocannabinol (THC), has risen independently of GLP's newfound fame due to the relaxation of legal hurdles across the nation to recreational cannabis usage. THC interacts with receptors in the endocannabinoid system, with the major ones being cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), both GPCRs. As these GPCR targets are becoming increasingly of interest due to these independent pathways, this study aimed to identify potential crossover between the endocannabinoid system and the GLP-1R system through molecular docking experiments. This was done using endogenous (2-AG and anandamide) and exogenous (THC) ligands of the endocannabinoid system , along with a proposed small oral agonist (danuglipron) of GLP-1R. Results indicated that danuglipron, a small GLP-1R agonist, had a higher binding affinity for CB1 and CB2 than any of the endogenous or exogenous ligands of the endocannabinoid system, suggesting the potential for cross-reactivity.