Computational insights into the antioxidant and antidiabetic mechanisms of cannabidiol: An in vitro and in silico study

The present study was aimed at investigating the molecular mechanism involved the antioxidant and antidiabetic activities of cannabidiol using in vitro and in silico models. The antioxidant activities of cannabidiol were determined by assaying its ability to scavenge 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical and reduce ferric ion (Fe³⁺). The antidiabetic activity of cannabidiol was determined by its ability to inhibit α-glucosidase activity. The DPPH scavenging activity of cannabidiol was further investigated using the Density Functional Theory (DFT) analysis. The molecular interactions of cannabidiol and α-glucosidase activity was determined via molecular docking and molecular dynamics simulation. Cannabidiol significantly scavenged DPPH radical and reduced Fe³⁺, with IC₅₀ values of 211.93 and 101.72 μg/mL, respectively. It also inhibited the activity of α-glucosidase, with an IC₅₀ value of 311.26 μg/mL. DFT analysis revealed sequential proton loss followed by electron transfer (SPLET) as the preferred mechanism by which cannabidiol scavenge DPPH, followed by hydrogen atom transfer (HAT) and single electron transfer followed by proton transfer (SET-PT). The highest occupied molecular orbital (HOMO) orbitals were delocalised on the benzene ring and O–H groups, while the lowest energy orbital (LUMO) orbitals were distributed on both the parent and substituent molecules. Cannabidiol bounded favourably to α-glucosidase enzyme, with ΔG, root mean square deviation (RMSD), root mean square fluctuation (RMSF) values of −28.49 kcal/mol, 1.36 Å and 0.835 Å as well as higher correlated motions. Therefore, the antioxidant activity of cannabidiol involves the abstraction of its H1 by the radical and delocalization of the radical's unpaired electron. Its antidiabetic activity can be attributed to the potent inhibitory effect on α-glucosidase, as well as its high affinity with the enzyme.