The field of hemp-derived compounds has been experiencing exponential growth, raising significant scientific, economic, and therapeutic challenges. Cannabinoids are classified into phytocannabinoids, endocannabinoids, and synthetic cannabinoids, all of which interact with various cellular targets, including the human cannabinoid receptors CNR1 and CNR2, members of the GPCR family. Among them, cannabidiol (CBD) has gained attention due to its potential effects on anxiety, pain, and inflammation. However, its interactions with these receptors remain poorly understood.
In this study, we used molecular modeling approaches to explore the interaction dynamics of CBD, Δ9-tetrahydrocannabinol (THC), and tetrahydrocannabiorcol (THC7) with both CNR1 and CNR2. After completing structural data through homology modeling and energy minimization, we performed molecular docking followed by molecular dynamics simulations in a neuronal membrane environment over multiple microseconds. Several activation markers were analyzed, including ionic lock disruption, toggle switch movement, and intracellular loop (ICL3) involvement.
Our results reveal complex activation dynamics. An active-like conformation of CNR1 was identified, characterized by a displacement of helix TM6 and a role of the ICL3 loop in receptor activation. Interestingly, CBD appears to facilitate access to these active states, despite its lack of classical agonist activity, suggesting a possible influence on the basal activity of CNR1. THC and THC7 exhibited distinct stabilization patterns, highlighting potential pharmacological differences. A comparative analysis of CNR2 revealed notable structural divergences in its activation pathway.
These findings provide new insights into CNR1 and CNR2 activation mechanisms and may contribute to a better understanding of phytocannabinoid pharmacology, with potential therapeutic implications.