Binding Modes and Selectivity of Cannabinoid 1 (CB1) and Cannabinoid 2 (CB2) Receptor Ligands

The cannabinoid (CB) receptors (CB₁R and CB₂R) represent a promising therapeutic target for several indications such as nociception and obesity. The ligands with nonselectivity can be traced to the high similarity in the binding sites of both cannabinoid receptors. Therefore, the need for selectivity, potency, and G-protein coupling bias has further complicated the design of desired compounds. The bias of currently studied cannabinoid agonists is seldom investigated, and agonists that do exhibit bias are typically nonselective. However, certain long-chain endocannabinoids represent a class of selective and potent CB₁R agonists. The binding mode for this class of compounds has remained elusive, limiting the implementation of its binding features to currently studied agonists. Hence, in the present study, the binding poses for these long-chain cannabinoids, along with other interesting ligands, with the receptors have been determined, by using a combination of molecular docking and molecular dynamics (MD) simulations along with molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations. The binding poses for the long-chain cannabinoids implicate that a site surrounded by the transmembrane (TM)2, TM7, and extracellular loop (ECL)2 is vital for providing the long-chain ligands with the selectivity for CB₁R, especially I267 of CB₁R (corresponding to L182 of CB₂R). Based on the obtained binding modes, the calculated relative binding free energies and selectivity are all in good agreement with the corresponding experimental data, suggesting that the determined binding poses are reasonable. The computational strategy used in this study may also prove fruitful in applications with other GPCRs or membrane-bound proteins.