3.2 Molecular Docking
Docking results of the viral virulence factors, namely, spike glycoprotein, NSP15 endoribonuclease and Main Protease 3CLpro; and the drug 2-deoxy-D-glucose (2-DG) as well as 2-DG derivative (1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose) are shown in Table 2 . These docking based E values have also been compared with that of the standard drugs (lopinavir, favipiravir and hydroxychloroquine). The Hex based docking results reveal that the E-value of docking of 2-DG with viral main protease 3CLpro (E value2-DG + Protease = -140.05 Kcal/mol) was found to be better than that of the standard drug lopinavir (E valueLopinavir + Protease = -124.00 Kcal/mol). Similarly, the docking of 2-DG with viral endoribonuclease also yielded significantly better binding energies (E value2-DG + Endoribonuclease = -168.65 Kcal/mol) as compared to that of the standard drug favipiravir (E valueFavipiravir + Endoribonuclease = -128.00 Kcal/mol). However, the binding energy of 2-DG with that of spike glycoprotein (E value2-DG + Spike glycoprotein = -118.31 Kcal/mol) was found to be moderately lower as compared to that of the tested standard drugs. It is obvious from the E-values that 2-deoxy-D-glucose binds spontaneously and irreversibly to main protease 3CLpro and viral endoribonuclease, wherein the binding efficiency of 2-DG has been found to be exceedingly better than that of lopinavir and favipiravir. Such significant binding affinity of 2-DG with that of SARS-CoV-2 viral receptors presumably indicates the probable mechanism of action of 2-deoxy-D-glucose as viral protease and endoribonuclease inhibitor. Viral protease is fundamental for continuing the viral life cycle of SARS-CoV-2 as it is required by the virus to catalyze the cleavage of viral polyprotein precursors which are ultimately necessary for viral capsid formation and enzyme production (Anand et al., 2003). Similarly, viral endonucleases are necessary for catalyzing the processing of viral RNAs and hence are required for enduring the process of viral replication (Ward et al., 2020). Henceforth, the 2-deoxy-D-glucose moiety contingently inactivates the viral protease, thereby inhibiting the process of viral capsid formation. Furthermore, 2-DG may also be responsible for withholding the action of viral endoribonuclease, thereby halting the process of viral replication altogether.
Moreover, the 2-DG derivative, namely, 1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose also showed an increase in the free energy of the complex with the viral receptors. The E-value of docking of 2-DG derivative with viral main protease 3CLpro (E value2-DG derivative + Protease = -187.64 Kcal/mol) was found to be better than that of the standard drug lopinavir (E valueLopinavir + Protease = -124.00 Kcal/mol). Similarly, the docking of 2-DG derivative with viral endoribonuclease (E value2-DG derivative + Endoribonuclease = -208.33 Kcal/mol) as well as spike glycoprotein (E value2-DG derivative + Spike glycoprotein = -173.89 Kcal/mol) yielded significantly better results as compared to that of favipiravir, wherein its E value is lower in both cases, i.e. , E valueFavipiravir + Endoribonuclease = -128.00 Kcal/mol; and E valueFavipiravir + Spike glycoprotein = -118.31 Kcal/mol. The 2-DG derivative exhibited significantly better binding values as compared to that of 2-DG itself. The derivative displayed spontaneous binding efficiencies while docking with viral protease, viral endonuclease and spike glycoprotein. The binding energy of 2-DG derivative was found to be comparable to that of hydroxychloroquine which has been proposed as the cornerstone for COVID-19 therapy. Hence, 1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose could presumably mitigate the virus completely as it could restrict viral entry into the host cell by inactivating the spike glycoprotein; halt viral capsid formation by inactivating the viral main protease; and cease viral replication by inactivating the viral endoribonuclease. Earlier studies have also indicated that glucopyranose derivatives are glycolysis inhibitors and cause mitochondrial oxidative phosphorylation, thereby indicating a probable antiviral role of 1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose (Jeon et al., 2020).