Unlocking the Reverse Targeting Mechanisms of Cannabidiol: Unveiling New Therapeutic Avenues

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC),
the
main components of Cannabis sativa plants, have attracted
a significant amount of attention due to their biological activities.
This study identified GPR18 as the target of partial agonist CBD activating
the p42/p44 MAPK pathway leading to migration of endometrial epithelial
cells. Induced fit docking (IFD) showed that the affinity of THC for
GPR18 is higher than that of CBD, and molecular dynamics (MD) simulations
showed that CBD–GPR18 complexes at 130/200 ns might have stable
conformations, potentially activating GPR18 by changing the distances
of key residues in its active pocket. In contrast, THC maintains “metastable”
conformations, generating a “shrinking space” leading
to full agonism of THC by adding mechanical constraints in GPR18’s
active pocket. Steered molecular dynamics (SMD) revealed GPR18’s
active pocket was influenced more by CBD’s partial agonism
compared with THC. This combined IFD–MD–SMD method may
be used to explain the mechanism of activation of partial or full
agonists of GPR18.