Inhibitory potential of gallic acid against SARS-CoV-2 main protease: A structure-function insight using combined spectroscopic and computational approach

The global pursuit of effective antiviral medicines against the main protease (Mpro) of SARS-CoV-2 has led to the exploration of natural compounds with inhibitory properties to fight against COVID-19. Gallic acid (GA), a bioactive phenolic compound, has been reported to exert effects against a range of respiratory viruses by the inhibition of viral enzymes crucial for replication. This research delved into the interplay between Mpro and GA, employing multidisciplinary biophysical, biochemical, and computational methodologies. The FRET based enzyme inhibition assay demonstrated that GA can effectively inhibit Mpro (IC₅₀ = 17.5 μM). The fluorescence spectroscopy performed to assess the binding parameters of the Mpro-GA interaction indicated the formation of the Mpro-GA complex with excellent binding (K = 1.17 × 10⁷ M⁻¹). The far-UV CD results demonstrated a concentration-dependent effect of GA on the secondary structure of Mpro. Molecular docking along with molecular dynamics simulations provided insights into the stability and conformational changes occurring at the binding interface, shedding light on the key structural determinants. The integration of experimental and computational data supports the notion that GA can critically perturb the topology of the main protease. This study paves the way for the development of antiviral drugs harnessing the power of natural compounds.