Summary
A novel respiratory pathogen, SARS-CoV-2 has recently received worldwide
attention and has been declared a public health emergency of global
concern. Entry of SARS-CoV-2 is mediated through the viral spike
glycoprotein (S2). Afterwards, the virus gets hold of the host cell
machinery by employing the use of viral main protease 3CLpro and NSP15
endoribonuclease. In the present in silico study, active site
mapping of the viral virulence factors was rendered by means of DoG Site
Scorer. The possibility of repurposing of 2-deoxy-D-glucose (2-DG), a
radio-chemo-modifier drug used for optimizing cancer therapy, and one of
its derivative (1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose, has
been investigated by conducting ligand-receptor docking. Binding pose
depictions of ligands and viral receptors were assessed by employing
molecular dynamics analysis. Molinspiration and Toxicity Estimation
Software tools were used to assess the drug likeliness, bioactivity
indices and ADMETox values. 2-DG can dock efficiently with viral main
protease 3CLpro as well as NSP15 endoribonuclease, thus efficiently
inactivating these viral receptors leading to incapacitation of the
SARS-CoV-2 virus. Such incapacitation was possible by means of formation
of a hydrogen bond between 2-DG and proline residues of viral protease.
The 2-DG derivative formed a hydrogen bond with the glutamine amino acid
residues of the viral spike glycoprotein. The present in silicostudy supports the potential benefits of using 2-DG and its
glucopyranose derivative as repurposed drugs/prodrugs for mitigating the
novel COVID-19 infection. Since both these moieties present no signs of
serious toxicity, further empirical studies on model systems and human
clinical trials to ascertain effective dose-response are warranted and
should be urgently initiated.
Keywords : 2-deoxyglucose, binding free energy, corona virus,
drug repurposing, molecular docking, SARS-CoV-2.
Abbreviations : 2-DG: 2-deoxy-D-glucose; ADMETox: Adsorption,
Distribution, Metabolism, Toxicity; CoV: Coronavirus; DARS: Decoys as
Reference State; FFT: Fast Fourier Transform; GPCR: G-protein coupled
receptor; MERS: Middle East Respiratory Syndrome; NSP: Non structural
protein; O.E.C.D.: Organisation for Economic Co-operation and
Development; PDB: Protein Data Bank; QSAR: Quantitative Structure
Activity Relationship; RCSB: Royal Collaborative Structural Biology;
SARS: Severe Acute Respiratory Syndrome; T.E.S.T.: Toxicity Estimation
Software Tool; TPSA: Total polar surface area; VIF: Viral infectivity
factor
Running title : 2-deoxy-D-glucose for combating COVID-19.