Uncovering potent natural products against Sars-Cov-2 main protease using structure-based virtual screening and...

The aim of the studies is to perform structure-based virtual screening against the main protease (Mpro) of SARS-CoV-2 to identify the novel natural product using in silico methods. The screening studies ranked the first 10 screened molecules in the docking method along with marketed drugs (NTR and LPV) and a known inhibitor (D95). These 10 molecules exhibited satisfactory ADME results. The stability studies using these 10 molecules were performed till 100 ns and extended three times using the MD simulation method. The triplicate MD simulation (three replicates) studies were found to have satisfactory stability parameters for the F35, like RMSD, RMSF, Rg, etc. The PCA demonstrated three replicates of the X77 and NTR displayed the substantial reproducible essential dynamics and stable conformational behaviour throughout the MD simulation. However, the F35 complex also followed the considerable overlap in motion or compact conformational sampling during MD simulation. Moreover, the zero-energy state structure of Mpro on the free energy landscape plot suggested that the novel natural product F35 also performed satisfactorily as compared to the known inhibitors (NTR, LPV, X77). Moreover, extended MD simulation was found that F35 is having binding potential similar to X77 (NTR > F35 ≈ X77) but need to be proved biologically using different in vitro/in vivo experiments. The F35 is a novel natural product never reported against Mpro SARS-CoV-2 to date. These computational studies suggested that the natural product-F35 (plant: Ornithogalum caudatum) followed the similar binding patterns and binding energy among the known Mpro inhibitors. Thus, F35 could be an alternative and complementary therapy against SARS-CoV-2 infection and exploited further for designing and searching for novel Mpro inhibitors.

The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00759-5.