Structure and Dynamics of Cannabinoid Binding to the GABA A Receptor

Research on medical cannabis is progressing, with several cannabinoids emerging as promising compounds for clinical use. The available evidence suggests that cannabinoids may modulate the glycine receptor (GlyR) and GABAA receptor, which are part of the pentameric ligand-gated ion channels (pLGICs) superfamily and facilitate chemical communication in the nervous system. In a previous study, we employed molecular dynamics (MD) simulations to elucidate the dynamics of the GlyR/Δ9-tetrahydrocannabinol (THC) complex and successfully identified a representative binding mode. Given the structural similarity between GlyR and GABAAR, we employed a similar strategy to investigate GABAAR-cannabinoid interactions. We initially assessed the binding mode of THC to GABAAR-α1β2γ2 at the equivalent binding site of the GlyR—that is, on its two α-subunits—as well as the impact of this binding on the channel´s dimensions. Our results indicate, first, that the binding modes of THC to GABAAR and GlyR exhibit comparable characteristics and, second, that THC may function as a potentiator of GABA activity due to a significant opening of the channel pore. Additionally, we aimed to reduce the overall computational cost associated with exploring binding modes. To this end, we developed and validated a simplified model comprising a single-monomer system for cannabinoid binding studies. This model proved to be accurate and cost-effective, accelerating the in silico screening process and allowing for the study of GABAAR-cannabinoid binding through docking and MD simulations. Moreover, the analysis of different cannabinoids in this system suggests that cannabigerol (CBG) and cannabichromene (CBC) could act as ligands for GABAAR, opening unexplored avenues for research.