Identification of CB1 Ligands among Drugs, Phytochemicals and Natural-Like Compounds: Virtual Screening and In Vitro Verification

Cannabinoid receptor
type 1 (CB1) is an important modulator of
many key physiological functions and thus a compelling molecular target.
However, safe CB1 targeting is a non-trivial task. In recent years,
there has been a surge of data indicating that drugs successfully
used in the clinic for years (e.g. paracetamol) show CB1 activity.
Moreover, there is a lot of promise in finding CB1 ligands in plants
other than Cannabis sativa. In this study, we searched
for possible CB1 activity among already existing drugs, their metabolites,
phytochemicals, and natural-like molecules. We conducted two iterations
of virtual screening, verifying the results with in vitro binding
and functional assays. The in silico procedure consisted of a wide
range of structure- and ligand-based methods, including docking, molecular
dynamics, and quantitative structure–activity relationship
(QSAR). As a result, we identified travoprost and ginkgetin as CB1
ligands, which provides a starting point for future research on the
impact of their metabolites or preparations on the endocannabinoid
system. Moreover, we found five natural-like compounds with submicromolar
or low micromolar affinity to CB1, including one mixed partial agonist/antagonist
viable for hit-to-lead phase. Finally, the computational procedure
established in this work will be of use for future screening campaigns
for novel CB1 ligands.