Elucidation of Partial Activation of Cannabinoid Receptor Type 2 and Identification of Potential Partial Agonist: Molecular Dynamics Simulation and Structure-Based Virtual Screening

Abstract Cannabinoid receptors type 2 (CB2R) is a member of class A G protein-coupled receptor (GPCRs) family and a component of the endocannabinoid system modulated by a psychoactive chemical from Cannabis sativa, partial agonist Δ9-tetrahydrocannabinol (Δ9-THC). Selective activation of CB2R allows for the treatment of inflammatory and immune-related conditions without the psychotropic effects of CB1R. While CB2R-selective agonists are available, CB2R partial agonists are scarce. Hence, the pharmacological difference between CB2R full agonist and partial agonist remains to be deciphered, prompting the search for novel partial agonists. Here, using an induced-fit docking approach, we built a partial agonist Δ9-THC bound CB2R system from the inactive CB2R structure (PDB ID: 5ZTY) and performed microsecond molecular dynamics (MD) simulations. The simulations reveal an upward shift of the “toggle switch” W6.48(258) and minor outward movement of the transmembrane helix 6 (TM6). The Dynamics network model identifies possible communication path between the ligand and the toggle switch” W6.48(258). Furthermore, to identify novel CB2R partial agonists, we conducted structure-based virtual screening of ZINC15 “Druglike” library containing 17,900742 compounds against 3 conformations derived from MD simulation of CB2R complexed with partial agonist Δ9-THC using Glide virtual screening protocol comprising various filters with increasing accuracy. The top 30 hits (10 compounds for each conformation) were subjected to molecular dynamics simulation, MM-GBSA binding energy calculations, and further ADMET prediction. Nine diverse compounds with higher MM-GBSA scores and good ADMET properties are proposed as novel potential CB2R partial agonists.