Distinct activation mechanisms regulate subtype selectivity of Cannabinoid receptors

Design of cannabinergic subtype selective ligands is challenging because of high sequence and structural similarities of cannabinoid receptors (CB1 and CB2). We hypothesize that the subtype selectivity of designed selective ligands can be explained by the ligand binding to the conformationally distinct states between cannabinoid receptors. Analysis of similar to 700 mu s of unbiased simulations using Markov state models and VAMPnets identifies the similarities and distinctions between the activation mechanism of both receptors. Structural and dynamic comparisons of metastable intermediate states allow us to observe the distinction in the binding pocket volume change during CB1 and CB2 activation. Docking analysis reveals that only a few of the intermediate metastable states of CB1 show high affinity towards CB2 selective agonists. In contrast, all the CB2 metastable states show a similar affinity for these agonists. These results mechanistically explain the subtype selectivity of these agonists by deciphering the activation mechanism of cannabinoid receptors.

Automated summary

Designing selective ligands for cannabinoid receptors (CB1 and CB2) is challenging due to their high sequence and structural similarities. In this study, we propose that the subtype selectivity can be explained by the binding of ligands to distinct conformational states between these receptors. By analyzing unbiased simulations using Markov state models and VAMPnets, we identify similarities and differences in the activation mechanism of CB1 and CB2. Our findings reveal the distinction in binding pocket volume changes during CB1 and CB2 activation and provide mechanistic insights into the subtype selectivity of agonists.