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).