In silico insights on the binding site and function of cannabinoids and cannabinoid acids on human 5-HT1A receptor

Previous studies reported that the acid congener of the cannabinoids, cannabidiolic acid, was approximately 1000 times more effective than the neutral congener, cannabidiol, in alleviating emesis. The biological actions of cannabinoids were proposed to be mediated by the enhancement of somatodendritic 5-HT 1A receptors. However, to date, the potential mechanism that may be involved in the enhancement of the 5-HT 1A activity by the acid congener is still lacking. To address this gap, molecular docking and molecular dynamics simulations were performed on different pairs of neutral and acidic cannabinoids in a human 5-HT 1A receptor model. Analyses showed that simulated cannabinoid acids (cannabidiolic acid and tetrahydrocannabivarinic acid) and tetrahydrocannabivarin were preferentially bound at the allosteric site of 5-HT 1A and were able to maintain the receptor in its active state when a full agonist, R(+)-8-OH-DPAT, was bound at the orthosteric site. Importantly, these results also suggest that the strong activity of cannabidiolic acid is not due to its strong affinity for the 5-HT 1A receptor but its positive allosteric modulation of the agonist activity on 5-HT 1A , presumably by blocking the exit of the orthosteric ligand, hence promoting continuous activation of the receptor. This study also demonstrates that cannabidiol and both neutral and acidic cannabigerol prefer binding at the orthosteric site and are potential partial agonists of 5-HT 1A . In conclusion, these findings propose that every cannabinoid, regardless of whether neutral or acidic, is unique on its own in terms of its binding and function. • CBD, CBG and CBGa are potential partial agonists of 5-HT 1A receptor. • CBD, CBG and CBGa may compete with orthosteric ligand for binding. • CBDa, THCV and THCVa are potential allosteric modulators of 5-HT 1A receptor. • CBDa, THCV and THCVa can block the exit of orthosteric ligand from its binding site. • MD + 7TM Open IC can accurately predict the activity of 5-HT 1A binding ligands.