Deciphering the Potential of Pre and Pro-Vitamin D of Mushrooms against Mpro and PLpro Proteases of COVID-19: An In Silico Approach

Abstract

Vitamin D's role in combating the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus causing COVID-19, has been established in unveiling viable inhibitors of COVID-19. The current study investigated the role of pre and pro-vitamin D bioactives from edible mushrooms against Mpro and PLpro proteases of SARS-CoV-2 by computational experiments. The bioactives of mushrooms, specifically ergosterol (provitamin D₂), 7-dehydrocholesterol (provitamin-D₃), 22,23-dihydroergocalciferol (provitamin-D₄), cholecalciferol (vitamin-D₃), and ergocalciferol (vitamin D₂) were screened against Mpro and PLpro. Molecular docking analyses of the generated bioactive protease complexes unravelled the differential docking energies, which ranged from -7.5 kcal/mol to -4.5 kcal/mol. Ergosterol exhibited the lowest binding energy (-7.5 kcal/mol) against Mpro and PLpro (-5.9 kcal/mol). The Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) and MD simulation analyses indicated that the generated complexes were stable, thus affirming the putative binding of the bioactives to viral proteases. Considering the pivotal role of vitamin D bioactives, their direct interactions against SARS-CoV-2 proteases highlight the promising role of bioactives present in mushrooms as potent nutraceuticals against COVID-19.

Keywords: SARS-CoV-2; edible mushrooms; in-silico studies; pre-vitamin-D; pro-vitamin-D.

Figure 1

Molecular docking 2D and 3D interaction representation between SARS-2 Mpro and (A) 7-dehydrocholesterol, (B) cholecalciferol, (C) ergocalciferol, (D) ergosterol, (E) 22,23-dihydroergocalciferol, and (F) 22,23-dihydroergosterol.

Figure 2

Molecular docking 2D and 3D interaction representation between SARS-2 PLpro and (A) 7-dehydrocholesterol, (B) cholecalciferol, (C) ergocalciferol, (D) ergosterol, (E) 22,23-dihydroergocalciferol, and (F) 22,23-dihydroergosterol.

Figure 3

The root-mean-square deviation (RMSD) analysis. (A) The RMS deviation of Mpro in the apo and ligand-bound states. (B) The RMS deviation of ligands coupled to Mpro’s active site. (C) The RMS deviation of PLpro in the apo and ligand-bound states. (D) The RMS deviation of ligands coupled to the active site of PLpro.

Figure 4

Root-mean-square fluctuations (RMSF) from the initial structures of (A) the main protease and main protease–ligand complexes and (B) papain-like protease and papain-like protease–ligand complexes during the simulation time. Time evolution plot of Rg for all Cα atoms in apo and holo states of (C) Mpro and (D) PLpro. Solvent accessible surface area (SASA) of (E) Mpro and complex and (F) PLpro and complex.

Figure 5

Hydrogen bond formation during the 100 ns simulation and hydrogen bond distribution between protease and ligand between Mpro and ligand molecules. (A) Hydrogen bond distribution; (B) no. of hydrogen bonds, PLpro and ligand molecules; (C) hydrogen bond distribution, and (D) no. of hydrogen bonds.