3.3 Ligand Receptor binding pose depictions
The best docking pose of 2-DG, and its derivatives with SARS-CoV-2 viral
receptors was also identified using Pose View tool so as to visualize
the interactions of the ligands with that of the residues present in the
active sites of the viral receptors. Both 2-deoxy-D-glucose and its
derivative were found to form salt bridges with the amino acid residues
of the viral receptors, namely, main protease 3CLpro and viral spike
glycoprotein, respectively. The orientational binding of the ligands and
the viral receptors showing the pose view and residue interactions have
been depicted in Fig. 3 . It was observed that the hydroxyl
group of 2-deoxy-D-glucose formed a hydrogen bond with the carbonyl
residue of Proline amino acid (108th position) found
in the viral main protease. In earlier studies it has been found that
the proline amino acid residues are found in the conserved domains of
HIV viral infectivity factor (Vif) and these proline-rich motifs are
therapeutic targets for neutralizing the human immunodeficiency virus
(Yang et al., 2003; Ralph et al., 2020). Chemical bridging of
2-deoxy-D-glucose and proline residues of viral main protease 3CLpro
present a similar case where proline residues were invariably bound and
neutralized, thereby possibly neutralizing the COVID-19 virus.
Similarly, the 2-DG derivative (1, 3, 4,
6-Tetra-O-acetyl-2-deoxy-D-glucopyranose) formed a hydrogen bond with
the amide group of Glutamine amino acid (804thposition) found in the viral spike glycoprotein. Reynard and Volchkov
have also previously highlighted that mutation or any change in the
glutamine residues of Ebola virus spike glycoprotein causes viral
neutralization (Reynard & Volchkov, 2015). In conclusion, the binding
interactions of 2-deoxy-D-glucose with viral main protease and 1, 3, 4,
6-Tetra-O-acetyl-2-deoxy-D-glucopyranose with viral spike glycoprotein
is now evident, as analysed by using Pose View tool.
2-deoxy-D-glucose and its derivative can influence several cellular
pathways, including glycolysis, glycosylation, endoplasmic stress
response (ER), phagocytosis and apoptosis. Both the moieties inhibit the
processes of glucose transport and glycolysis by competing with glucose.
Competitive uptake of 2-DG or its derivative in the infected cell leads
to the formation of 2-deoxy-d-glucose-6-phosphate (2-DG-6-P) by means of
hexokinase enzyme. 2-DG-6-P cannot be further metabolized, thereby
hampering the bioenergetic process of ATP production by glycolysis
(Sharma et al., 1996); inactivating the glycolytic enzymes; inducing
cell cycle arrest and ultimately leading to inactivation of nCoV-19 in
infected cells (Maher et al., 2004; Pajak et al., 2020). The depletion
of ATP levels leads to activation of AMP-activated protein kinase
(AMPK). Such activation will lead to phosphorylation of proteins of the
mTOR kinase complex (mammalian target of rapamycin kinase, mTORC). As a
consequence, expression of p53 is induced which ultimately promotes cell
cycle arrest (G1 phase arrest) in virus infected cells. All these
factors (glycolysis inhibition, ATP depletion and cell cycle arrest)
cause a sensitized response leading to the upregulation of TNF
expression, ultimately leading to an apoptotic response. Moreover, both
2-DG and its tetra-acetate glucopyranose derivative escalate the
production of reactive oxygen species, ultimately leading to virus
infected cell death (Fig. 4 ) (Zhang et al., 2015; Pajak et al.,
2020).