Evaluating Allosteric Perturbations in Cannabinoid Receptor 1 by In Silico Single-Point Mutation.

Cannabinoid receptor 1 (CB1) is a promising drug target involved in many physiological processes. Using atomistic molecular dynamics (MD) simulations, we examined the structural effect of F237L mutation on CB1, a mutation that has qualitatively similar effects to allosteric ligand ORG27569 binding. This mutation showed a global effect on CB1 conformations. Among the observed effects, TM6 outward movement and the conformational change of the NPxxY motif upon receptor activation by CB1 agonist CP55940 were hindered compared to CB1. Within the orthosteric binding site, CP55940 interactions with CB1 were altered. Our results revealed that allosteric perturbations introduced by the mutation had a global impact on receptor conformations, suggesting that the mutation site is a key region for allosteric modulation in CB1.