Computational Insights into the Agonist Activity of Cannabinoid Receptor Type-2 Ligands Using Molecular Dynamics Simulation

Cannabinoid (CB) receptors belong to the G protein-coupled receptor (GPCR) family and were activated by endogenous, phytogenic and synthetic modulators. The CB receptors are involved in a variety of physiological processes, including appetite, pain sensation, mood, memory, etc. The potency of ligands with receptors provides the path through which the latter show agonist, antagonist, or inverse agonist behaviour. Due to the unavailability of crystal structure of CB type-2 (CB2) receptor, we used multiple template comparative homology modelling algorithms to construct 3D models for the same. We performed docking and molecular dynamics simulation study of four synthetic drugs in both cannabinoid type-1 (CB1) and CB2 receptors. These ligands show agonist activity with the CB2 receptor and activates it completely. The results are compared with the CB1 receptor. Molecular properties of the ligands, including molecular, polar and solvent-accessible surface areas, and intramolecular hydrogen bonds were evaluated using molecular dynamics simulations. Our finding demonstrates that the ligand AM-1221 shows the highest binding affinity (–12.73 k cal/mol), whereas UR-144 shows the lowest (–9.83 k cal/mol) towards the CB2 receptor. These findings should stimulate the design of ligands with distinct pharmacological properties associated with the CB2 receptor.