The agonist binding mechanism of human CB2 receptor studied by molecular dynamics simulation, free energy calculation...

CB2-selective agonists have drawn attention in drug discovery, since CB2 becomes a promising target for the treatment of neuropathic pain without psychoactive or other CNS-related side effects. However, the lack of experimental data of the 3D structures of human cannabinoid receptors hampers the understanding of the binding modes between ligands and CB2 by traditional methods. In the present work, combinational molecular modeling studies including flexible docking, MD simulations and free energy calculations were performed to investigate the interaction modes and mechanism of CB2-unselective agonist CP55940 and CB2-selective agonist GW842166X, separately binding with the homology model of CB2 in a DPPC/TIP3P simulated membrane environment. The binding free energies calculated by MM-PBSA method give an explanation for the activity differences of the studied ligands. Binding free energies decomposition by MM-GBSA method shows that the van der Waals interaction is the dominant driving force during the binding process. Our MD simulations demonstrate that Phe197 could be a critical residue for the binding of CB2-selective agonists. Furthermore, by using the MD simulated binding conformer as a template, the 3D-QSAR studies were performed with the comparative molecular field analysis (CoMFA) approach on a set of GW842166X analogues. A combinational exploration of both CoMFA steric and potential contour maps for CB2 affinities and the MD studied interaction modes sheds light on the structural requirements for CB2 agonists and serves as a basis for the design of novel CB2 agonists.