Computationally Rationalising the Conformational Dynamics of Pseudo-Endocannabinoid Receptors CB₁ and CB₂ with Cannabidiol

This study provides a comprehensive analysis of the conformational dynamics of pseudo-endocannabinoid receptors (p-CBRs) CB1 and CB2 in response to ligand binding. The ligands studied include N-arachidonoyl dopamine (NADA), Cannabidiol (CBD), known agonists (FUB-MDMB and E3R), and inverse agonists (Taranabant and AM630). Using homology models based on crystal structures (PDB ID: 5U09 for CB1 and 5ZTY for CB2), molecular docking, and molecular dynamics (MD) simulations, the research validates the structural integrity and dynamic behaviours of these pseudo-receptors. Induced-fit docking revealed NADA as having the highest binding affinity for both receptors, with docking scores of −13.92 kcal/mol for CB1 and −13.32 kcal/mol for CB2, facilitated by key hydrogen bond interactions. MD simulations over 250 ns at ~298 K showed successful equilibration, indicating the most stable interaction for NADA, thereby further validating the models. CB1 and CB2 exhibited distinct conformational responses to ligands, with Cα RMSD and Cα RMSF analyses suggesting a more rigid binding pocket for CB1 and a flexible binding pocket for CB2. These findings highlight the significance of receptor behaviour and dynamics in the development of cannabinoid-based therapeutics, supporting the potential of CBD and NADA as modulators for CB1 and CB2, respectively.