In silico exploration of disulfide derivatives of Ferula foetida oleo-gum (Covexir®) as promising therapeutics against SARS-CoV-2

Highlights

• In silico study of the binding mechanism of disulfide derivatives isolated from Ferula foetida to SARS-CoV-2 main protease.

• The van der Waals (vdW) energy plays the main role in the interaction of hotspot residues with the inhibitors.

• The disulfides mainly interacted with HIS41, MET49, CYS145, HIS64, MET165, and GLN189 residues of SARS-CoV-2 main protease.

• The electron density values for MET49-ligand interactions is higher than the other residue-ligand complexes.

Abstract

Although vaccines have been significantly successful against coronavirus, due to the high rate of the Omicron variant spread many researchers are trying to find efficient drugs against COVID-19. Herein, we conducted a computational study to investigate the binding mechanism of four potential inhibitors (including disulfide derivatives isolated from Ferula foetida) to SARS-CoV-2 main protease. Our findings revealed that the disulfides mainly interacted with HIS41, MET49, CYS145, HIS64, MET165, and GLN189 residues of SARS-CoV-2 main protease. The binding free energy decomposition results also showed that the van der Waals (vdW) energy plays the main role in the interaction of HIS41, MET49, CYS145, HIS64, MET165, and GLN189 residues with the inhibitors. Furthermore, it is found that the Z-isomer derivatives have a stronger interaction with SARS-CoV-2, and the strongest interaction belongs to the (Z)-1-(1-(methylthio)propyl)-2-(prop-1-enyl)disulfane (ΔG = −18.672 kcal/mol). The quantum mechanical calculations demonstrated that the second-order perturbation stabilization energy and the electron density values for MET49-ligand interactions are higher than the other residue-ligand complexes. This finding confirms the stronger interaction of this residue with the ligands.