Cannabinoid receptors type 2 (CB2) 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, Δ9-tetrahydrocannabinol (Δ9-THC). While agonist and antagonist bound structures have become available recently, partial agonist bound CB2 structure is yet to be resolved, to date. Here, using induced-fit docking approach, we built a partial agonist Δ9-THC bound CB2 system from the inactive CB2 structure (PDB ID: 5ZTY) and performed microsecond molecular dynamics (MD) simulations. The simulations reveal an upward shift of the “toggle switch” W2566.48 and minor outward movement of the transmembrane helix 6 (TM6). Dynamics network model identifies possible communication path between the ligand and the toggle switch” W2566.48. These findings show the role of MD simulation in characterizing partial activation of CB2, and thus may be used for the design of therapeutic ligands against the receptor. Using the crystal conformation plus two MD conformations, we conducted structure-based virtual screening of ZINC “Druglike” library containing 17,900742 compounds using Glide virtual screening protocol comprising various filters with increasing accuracy. The top 30 hits were subjected to molecular dynamics simulation, MM-GBSA binding energy calculations, and further ADMET prediction. A total of 10 diverse compounds are proposed as novel potential CB2 partial agonists.

Probing partial activation of cannabinoid receptor type 2 and identification of novel partial agonist by structure-based virtual screening and molecular dynamics simulation

ACS Spring 2022

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