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

Oscar Díaz; Pedro Renault; Jesús Giraldo

doi:10.1021/acsomega.2c04980

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

ACS Omega. 2022 Oct 14;7(42):37873-37884. doi: 10.1021/acsomega.2c04980. eCollection 2022 Oct 25.

Authors

Oscar Díaz^{1

2

3}, Pedro Renault^{1

2

3}, Jesús Giraldo^{1

2

3}

Affiliations

¹ Laboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
² Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid 28029, Spain.
³ Unitat de Neurociència Traslacional, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT), Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.

Abstract

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 wt 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.