Distinct activation mechanisms regulate subtype selectivity of Cannabinoid receptors.

ABSTRACT: 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 ~ 700 μs 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

SUBMITTER: Dutta S 

PROVIDER: S-EPMC10163236 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature