Journal
MOLECULES
Volume 27, Issue 18, Pages -Publisher
MDPI
DOI: 10.3390/molecules27186127
Keywords
SARS-CoV-2; COVID-19; main protease (M-pro); minor cannabinoids; decarboxylation; structure and activity relationship; surface plasmon resonance; binding
Funding
- Rhode Island Institutional Development Award (IDeA) Network of Biomedical Research Excellence from the National Institute of General Medical Sciences of the National Institutes of Health [P20GM103430]
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This study confirms the inhibitory activity of a library of minor cannabinoids on SARS-CoV-2 M-Pro through biochemical analysis and molecular docking techniques. It also reveals that the anti-M-Pro effects of cannabinoids are influenced by decarboxylation and the length of the alkyl side chain.
The replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by its main protease (M-pro), which is a plausible therapeutic target for coronavirus disease 2019 (COVID-19). Although numerous in silico studies reported the potential inhibitory effects of natural products including cannabis and cannabinoids on SARS-CoV-2 M-pro, their anti-M-pro activities are not well validated by biological experimental data. Herein, a library of minor cannabinoids belonging to several chemotypes including tetrahydrocannabinols, cannabidiols, cannabigerols, cannabichromenes, cannabinodiols, cannabicyclols, cannabinols, and cannabitriols was evaluated for their anti-M-pro activity using a biochemical assay. Additionally, the binding affinities and molecular interactions between the active cannabinoids and the M-pro protein were studied by a biophysical technique (surface plasmon resonance; SPR) and molecular docking, respectively. Cannabinoids tetrahydrocannabutol and cannabigerolic acid were the most active M-pro inhibitors (IC50 = 3.62 and 14.40 mu M, respectively) and cannabigerolic acid had a binding affinity K-D = 2.16 x 10(-4) M). A preliminary structure and activity relationship study revealed that the anti-M-pro effects of cannabinoids were influenced by the decarboxylation of cannabinoids and the length of cannabinoids' alkyl side chain. Findings from the biochemical, biophysical, and computational assays support the growing evidence of cannabinoids' inhibitory effects on SARS-CoV-2 M-Pro.
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