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Glucose antimetabolite 2-Deoxy-D-Glucose and its derivative as promising candidates for tackling COVID-19: Insights derived from in silico docking and molecular simulations

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Abstract

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 silico study 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.
Posted on Authorea 31 Mar 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158567174.40895611 | This a preprint and has not been peer reviewed. Data may be preliminary.
Glucose antimetabolite 2-Deoxy-D-Glucose and its derivative as
promising candidates for tackling COVID-19: Insights derived
from in silico docking and molecular simulations
Acharya Balkrishna1, Pallavi Thakur1, Shivam Singh1, Swami Dev1, Viney Jain2, Anurag
Varshney1, and Rakesh Sharma3
1Patanjali Ayurved Ltd
2Jain Vishwa Bharti Institute
3Saveetha Institute of Medical and Technical Sciences
April 28, 2020
Abstract
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 silico study 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.
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.: Or-
ganisation for Economic Co-operation and Development; PDB: Protein Data Bank; QSAR: Quantitative
Structure Activity Relationship; RCSB: Royal Collaborative Structural Biology; SARS: Severe Acute Respi-
ratory Syndrome; T.E.S.T.: Toxicity Estimation Software Tool; TPSA: Total polar surface area; VIF: Viral
infectivity factor
1. Introduction
The Corona virus (COVID-19), which sprung up in China during the late November, 2019, has shown a
burgeoning spread since then as it has been known to infect more than 8,03,011 people around the world,
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resulting in nearly 39,025 deaths as of 31 March, 2020 (Shao, 2020; WHO, 2020). It has been found to spread
in about 201 countries within a short time span of three months and hence, has been declared a pandemic
by the World Health Organization on 11th of March, 2020 (Cucinotta & Vanelli, 2020).
Coronaviruses presents a large family of enveloped RNA (non-segmented, positive sense) viruses that cause
zoonotic respiratory or occasional gastrointestinal infections in humans, wherein camels, cattle, bats and
cats may serve as reservoirs of viral transmission (Ye et al., 2020). The earlier timeline of spread of Coro-
naviruses have suggested that mainly 3 outbreaks of deadly pneumonia have been caused by Coronaviruses
in the 21st Century. These pathogenic serotypes of Coronaviruses have been named as SARS-CoV (Severe
Acute Respiratory Syndrome causing Coronavirus, outbreak in 2002); MERS-CoV (Middle East Respiratory
Syndrome causing Coronavirus, outbreak in 2012); and SARS-CoV-2 (Novel Beta-Coronavirus, outbreak in
2019) (Guarner, 2020). Genomic analysis have delineated the phylogenetic similarity between SARS-CoV
and SARS-CoV-2, however, the latter shows a mutational degree of genomic diversification, mainly in the
NSP domains (16 non-structural protein domains). Such mutations in the NSP domains of SARS-CoV-2
may be responsible for the differences in the host responsiveness, transmissibility and fatality of COVID-19
(Fung et al., 2020).
Analyzing the early history of SARS-CoV-2, it has been found that the virus got transmitted from animals
to humans as several cases of COVID-19 disease transmission were directly linked to seafood and live animal
ingestion in Wuhan, China (Jiang et al., 2020; Ward et al., 2020). It has also been found that the SARS-
CoV-2 bears nearly 96.2% similarities with that of the bat CoV RaTG13, thereby indicating bats to be the
natural reservoir of this virus (Zhou et al., 2020). Consequently, person-to-person spread of infection began
through direct contact with the infected individuals and via respiratory droplets (Carlos et al., 2020). Some
investigations have also suggested that SARS-CoV-2 may be present in feces of infected individuals and even
after the patient is cured, thereby indicating a feco-oral route of viral transmission as well (Yeo et al., 2020).
There are different stages of transmission of this virus, i.e. , contracting the disease upon travelling to the
virus-hit countries (Stage 1); local transmission by coming in contact with patients with a foreign travel
history (Stage 2); community transmission with difficulty in tracing the actual source of infection (Stage 3);
and ultimately occurrence of an epidemic, wherein the disease spreads at an alarmingly high rate and hence
becomes unlikely to be controlled. Italy and China have unfortunately reached the stage 3 of transmission,
wherein the death tolls are constantly increasing with rapidly rising new cases of infection. India is still
at stage 2 of COVID-19 outbreak and hence the disease transmission can be restricted by adopting proper
quarantine and isolation measures (WHO, 2020; Jiang et al., 2020).
SARS-CoV-2 possesses a high magnitude of risk owing to its massive transmission rate (~3%), high case
fatality rate (~4.3 - 11%, however the fatality rate may change), longer half life of virus (4-72 hours), nosoco-
mial mode of transmission (~79% transmission in hospitals) and asymptomatic mode of transmission (~2-14
days of incubation). The most common symptoms of COVID-19 include fever, malaise, nasal congestion,
dry cough, sore throat, dyspnoea, diarrhoea and multiple organ complications. However, some people serve
as asymptomatic carriers of the disease. Such asymptomatic cases of COVID-19 are the most difficult to
diagnose and thereupon treat. Although the defined symptoms appear to be mild, however, there have
been reported illnesses ranging from mild to severe conditions, and even death (Huang et al., 2020; Kim,
2020; Ralph et al., 2020). Despite several research efforts, there are yet no specific antiviral medications and
vaccines available for fighting with COVID-19. Many ongoing clinical trials are currently being conducted to
identify the most propitious drug candidate against COVID-19. The most acclamatory way of identifying the
propitious drug candidates for COVID-19 depends on understanding the pathophysiology of SARS-CoV-2
(Guo et al., 2020).
The first step of attachment and entry of Coronaviruses is dependent on the binding of SARS-CoV-2 spike
glycoprotein (S2) to cellular receptors (Angiotensin converting enzyme 2, ACE2) of the host. Secondly, after
entry into the host cell, the virus starts replicating with the aid of viral nuclease (NSP15 endoribonuclease)
and protease (Main Protease 3CLpro). All these said viral virulence factors are vital for the viral life cycle
(Liu et al., 2020). Hence, unraveling the pathogenesis of these virulence factors might provide insights into
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the etiology of COVID-19 and reveal therapeutic targets (Fig. 1 ).
Although, the structure and sequence of these viral virulence factors are known and drug screening is
continuously being conducted by targeting these virulence factors. However, yet there are no approved
drugs for effectively managing COVID-19 infection. WHO has recently announced restricted use permission
for repurposed anti-HIV, anti-malarial, anti-flu and anti-Ebola drugs (Guo et al., 2020; Senathilake et al.,
2020). Considering such a considerable emergency of this outbreak, the current in silico study is aimed at
investigating the possibilities of a glucose anti-metabolite, 2-deoxy-D-glucose (2-DG) as a repurposed drug
for the treatment of novel SARS-CoV-2 virus. Post entry of virus, the host cells have been observed to
undergo metabolic reprogramming to meet the increased demand of nutrients and energy for replication of
the virus, wherein 2-DG might serve as a probable drug candidate as it acts as a dual inhibitor of glycolysis as
well as glycosylation (Gualdoni et al., 2018). 2-DG has already been granted permission for clinical trials, as
evidenced from previously published results (Mohanti et al., 1996; Vijayaraghavan et al., 2006; Dwarkanath
et al., 2009).
In the present study, the drug-like potential of 2-DG will be studied by targeting SARS-CoV-2 spike glyco-
protein (S2), viral nuclease (NSP15 endoribonuclease) and protease (Main Protease 3CLpro). The binding
mechanism of 2-DG with the said viral virulence factors will be assessed by means of in silico molecular
docking as well as pharmacophore modeling. Moreover, another tetra-acetate glucopyranose derivative of
2-DG (1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose) has also been assessed for studying its binding
affinities with the said viral virulence factors. The rationale for selecting this tetra-acetate glucopyranose
derivative as probable antiviral drug is dependent on its activity of impairing glycolysis and glycosylation.
Hence, this derivative can possibly be used as a prodrug for 2-DG (Jeon et al., 2020; Pajak et al., 2020).
One such prodrug of 2-DG, namely, 3,6-di-O-acetyl-2-deoxy-d-glucose has been developed in Dr. Waldemar
Priebe’s laboratory. This compound is currently being tested as an antiviral drug for targeting the novel
Coronavirus (Priebe et al., 2018; Keith et al., 2019; Pajak et al., 2020). Similar plan of repositioning 2-
deoxy-D-glucose and 1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose has been presented in the present
study, wherein all the molecular interactions of 2-DG and 2-DG derivative have been compared with the
currently used anti-retroviral drugs, i.e. , lopinavir; anti-flu drug, i.e. , favipiravir; and anti-malarial drug,
i.e. , hydroxychloroquine. The detailed molecular interactions and probable modes of action of 2-DG and
its prodrug have also been discussed in the present manuscript.
2. Materials and Methods
Conduction of the present in silico study has been made possible by the assistance of several databases includ-
ing PubChem (https://pubchem.ncbi.nlm.nih.gov/), RCSB Protein Data Bank (https://www.rcsb.org/) and
Proteins Plus Server (https://proteins.plus/); and softwares like Argus lab (http://www.arguslab.com/arguslab.com/ArgusLab.html),
Molinspiration (https://www.molinspiration.com/), Open Babel (http://openbabel.org), Hex (http://hex.loria.fr/),
and Toxicity Estimation Software Tool (https://www.epa.gov/chemical-research/toxicity-estimation-software-
tool-test). PubChem is an open chemistry database that provides two-dimensional chemical information
about the ligands being used in this study (Butkiewicz et al., 2013). The RCSB Protein Data Bank is a
global archive of three-dimensional structural data of biomolecules, per say viral receptors in this study (Rose
et al., 2015). Proteins Plus server is a common online server for computational drug modeling, wherein one
of its counterparts, namely, Pose View is used to visualize receptor structures and create pose depictions of
ligand-receptor binding. Moreover, another counterpart of Proteins Plus server, namely, DoG Site Scorer is
used to predict the active binding sites and druggability of binding pockets of receptors (F¨ahrrolfes et al.,
2017; Volkamer et al., 2012). Argus lab is molecular modeling software which is mainly used to visualize
the receptors as well as ligands and customize both of them for docking (Joy et al., 2006). Molinspiration is
online chemiinformatics software focused on calculating the molecular properties of ligands and predicting
their bioactivity properties (Jarrahpour et al., 2012). OpenBabel is an open platform for inter-converting
chemical file formats, thereby aiding in converting the 2D structure of ligands to 3D pdb structure and
hence customizing them for molecular docking (Samdani & Vetrivel, 2018). Hex is an interactive molecular
docking program for calculating the binding energies of interaction between receptors and ligands (Ritchie &
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Venkatraman, 2010). Toxicity Estimation Software Tool is a Quantitative Structure Activity Relationships
(QSAR) which is used to estimate the toxicity of ligands based on the molecular descriptors of the ligands
(Barron et al., 2012).
2.1 Preparation of 3D structure of viral virulence factors as receptors
The crystal structures of SARS-CoV-2 spike glycoprotein (S2; PDB code: 6VSB), viral nuclease (NSP15
endoribonuclease; PDB code: 6VWW) and protease (Main Protease 3CLpro; PDB code: 1Q2W) were
obtained from RCSB Protein Data Bank (https://www.rcsb.org/). Hydrogen atoms were introduced in
all these 3D structures using Argus Lab (4.0.1), so as to customize the viral receptors for rigid docking
(http://www.arguslab.com/arguslab.com/ArgusLab.html).
2.2 Preparation of 3D structure of 2-DG and 2-DG derivative as ligands
The structure of 2-deoxy-D-glucose and 2-DG derivative (1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose)
were downloaded in xml format from PubChem database and structures were validated (Butkiewicz et
al., 2013). Hydrogen atoms were introduced into the ligands structure using Argus lab (4.0.1), so as to
customize them for rigid docking. The hydrogenated ligand molecules were then converted into pdb format
using Open Babel (2.4) interface (openbabel.org/docs/dev/OpenBabel.pdf), as required for rigid docking.
Similarly, 3D structures of standard chemotherapeutic agents (lopinavir, favipiravir, hydroxychloroquine)
were also customized for docking.
2.3 Active site analysis of viral virulence factors
DoG Site Scorer, a web based tool (https://proteins.plus/), was used to predict the possible binding sites
in the 3D structure of spike glycoprotein, viral nuclease and viral main protease. Predictions with DoG Site
Scorer were based on the difference of gaussian filter to detect potential pockets on the protein surfaces and
thereby splitting them into various sub-pockets. Subsequently, global properties, describing the size, shape
and chemical features of the predicted pockets were calculated so as to estimate simple score for each pocket,
based on a linear combination of three descriptors, i.e ., volume, hydrophobicity and enclosure. For each
queried input structure, a druggability score between 0-to-1 was obtained. Higher the druggability score,
higher the physiological relevance of the pocket as potential target (Volkamer et al., 2012).
2.4 Molecular Docking and Ligand Receptor Binding analysis
The docking analysis of pdb structures of 2-deoxyglucose and its analogue (1, 3, 4, 6-Tetra-O-acetyl-2-
deoxy-D-glucopyranose) with viral receptors (spike glycoprotein, viral nuclease and viral main protease) was
carried by Hex Cuda 8.0.0 software. Receptor and Ligand files were imported in the software (Harika et
al., 2017). The grid dimension of docking was defined according the to the binding site analysis of DoG
Site Scorer (Volkamer et al., 2012). Graphic settings and Docking parameters were customized so as to
calculate the binding energies (E values) of ligand receptor docking. The parameters used for the docking
process were set as (i) Correlation type: Shape + Electro + DARS, (ii) FFT mode: 3D fast lite, (iii) Grid
Dimension: 0.6, (iv) Receptor range: 180°, (v) Ligand range: 180°, (vi) Twist range: 360°. The best docked
conformations with lowest docking energy were selected for further MD simulations using Pose View for
creating pose depictions of selected ligand-receptor binding (Ezat et al., 2014). Molecular Docking and MD
simulations for the standard chemotherapeutic agents (lopinavir, favipiravir, hydroxychloroquine) were also
conducted. The MM-PBSA method was used to compute the binding free energy of receptor-ligand docking
during simulation. In this study, the binding free energy of the receptors to ligands was calculated using the
GROMACS tool, wherein the binding free energy of the receptor and ligand was defined as
ΔGbinding =ΔGcomplex – (ΔGreceptor +ΔGligand)
For each subunit, the free energy, G, can be presented as summation of mechanical potential energy (Elec-
trostatic and Vander Waals interaction) and solvation free energy (Gpolar + Gnonpolar ), wherein the total
entropy is excluded from the total value (Weis et al., 2006).
2.5 Molinspiration based Molecular property and Bioactivity analysis
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Molinspiration software was used to analyze molecular descriptors and bioactivity scores of the ligands and
standard chemotherapeutic agents, namely, MiLog P, Total polar surface area (TPSA), molecular weight,
number of atoms, number of rotatable bonds, number of hydrogen bond donors and acceptors. Bioactivity
of the ligands was also checked by using Molinspiration which can analyze the activity score of GPCR
ligands, kinase inhibitors, ion channel modulators, enzymes and nuclear receptors. Ligands were loaded in
the Molinspiration software in SMILES format and the molecular descriptor as well as bioactivity analysis
was conducted (Jarrahpour et al., 2012).
2.6 In silico Toxicity estimation
Ligands (2-DG and 2-DG derivative) and standard chemotherapeutic agents (lopinavir, favipiravir, and
hydroxychloroquine) were uploaded in the Toxicity Estimation Software Tool in sdf format. Oral rat LD50 ,
Bioconcentration Factor, Developmental Toxicity and Ames Mutagenicity were estimated using consensus
method of QSAR analysis (Barron et al., 2012).
3. Results & Discussion
3.1 Active site analysis
Active site analysis of SARS-CoV-2 spike glycoprotein (S2), viral nuclease (NSP15 endoribonuclease) and
protease (Main Protease 3CLpro) as conducted by DoG Site Scorer indicated that there are various active
pockets within the studied viral virulence factors with druggability ranging from 0.12 to 0.86 (Table 1 ).
It was found that pockets P 11 (Drug score: 0.847), P 1 (Drug score:0.860) and P 0 (Drug score: 0.805)
were energetically favourable for performing further molecular docking studies with the viral receptors being
spike glycoprotein, NSP15 endoribonuclease and Main Protease 3CLpro, respectively. While conducting the
active site analysis, the DoG Site Scorer tool analysed the heavy atom coordinates on the surface of the 3D
structure of the respective viral receptors. Depending on these atomic coordinates, a hypothetical grid was
spanned by outruling the chances of any spatial overlap of the grid with the heavy atoms. Furthermore, the
tool engages in applying a Gaussian filter to the defined grids, so as to identify spherical pockets of binding.
Druggability score (0-1) of the selected spherical pockets are deduced on the basis of their surface area,
volume, enclosure and hydrophobicity. As a general rule, higher druggability score is indicative of a more
druggable pocket (Volkamer et al., 2012). The most druggable pockets of SARS-CoV-2 spike glycoprotein,
NSP15 endoribonuclease and main protease 3CLpro have been elucidated inFig. 2 .
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
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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).
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, glycosyla-
tion, 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 deriva-
tive 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
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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 es-
calate the production of reactive oxygen species, ultimately leading to virus infected cell death (Fig. 4 )
(Zhang et al., 2015; Pajak et al., 2020).
3.4 Molecular property analysis
After analyzing the binding energies and ligand-receptor binding pose depictions, it was requisite to evaluate
the drug likeliness of the ligands. Analysis of molecular descriptors is necessary in elucidating the pharma-
cokinetic parameters of the drugs such as absorption, distribution, metabolism, and excretion. Molinspiration
software was used to analyze the Lipinski Rule of Five, including the Log P value (partition coefficient),
molecular weight, polar surface area, number of hydrogen bond donor and number of hydrogen bond accep-
tor. According to the Lipinski’s rule, a drug like moiety should have a low molecular weight ([?] 500 D), log P
value [?] 5, number of hydrogen bond acceptors [?]10, and number of hydrogen bond donors [?]5. A bioactive
druggable molecule should ensue to at least 4 of the 5 Lipinski rules (Zhang & Wilkinson, 2007). In the
present study, it was found that 2-deoxy-D-glucose and 1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose
befalls within the said permissible limits of Lipinski rules and hence, both these drugs can be said to possess
satisfactory oral bioavailability (Table 3 ).
3.5 Bioactivity analysis
Molinspiration was used to virtually screen the biological activity of drug moieties, per say 2-DG and 2-
DG derivative in the present study. The fundamental principle behind this in silico bioactivity screening
is the identification of substructure(s) responsible for endowing pharmacological features (GPCR binding
ability, ion channel modulation potential, kinase inhibition activity, nuclear receptor binding potential, and
protease inhibition) to the drug molecules being studied. The bioactivity score of the ligands and standard
chemosynthetic moieties is presented in Table 4 . In general, if the bioactivity score for a particular target is
more than 0.0, then the said drug moiety is considered to be highly active. Additionally, a bioactivity score
of a ligand lying between -5.0 and 0.0 is considered to be moderately active. However, bioactivity scores
of ligands below -5.0 render it to be inactive (Singh et al., 2013). As observed in Table 4, the bioactivity
scores of 2-DG for most of the bioactivity descriptors were below -0.5, thereby indicating its inactivity
towards those targets. However, 2-DG possessed moderate bioactivity as ion channel modulator (Bioactivity
score Ion channel modulator ˜ -0.14) and protease inhibitor (Bioactivity score Protease inhibitor ˜ -0.37). This
bioactivity score of 2-DG is in corroboration with the molecular docking results which also suggest 2-DG to
be a significant protease inhibitor (E 2-DG + Protease = -140.05 Kcal/mol). The antiviral effect of 2-DG has
also been recognized in previous studies. Inhibition of multiplication has been reported for some enveloped
viruses such as influenza virus, sindbis virus, semliki forest virus, herpes simplex virus, respiratory syncytial
virus and measles virus (Kang & Hwang, 2006; Krol et al., 2017). Furthermore, 2-DG eliminated genital
herpes from most of the tested patients. It also alleviated the severity of infection of calves with respiratory
syncytial virus and infectious of bovine rhino-tracheitis virus (Leung et al., 2012). According to all these
earlier studies, inhibition of viral envelope biosynthesis and virion assembly due to blocked glycosylation
of membrane proteins appears to be the major mechanism of 2-DG for virus attenuation. This has been
supported by altered gel electrophoresis profiles of membrane proteins as well as denuded appearance of
budding particles shown by electron microscopy. Studies also suggest that 2- DG can also suppress viral
gene expression or viral replication (Camarasa et al., 1986; Kang & Hwang, 2006; Leung et al., 2012; Krol
et al., 2017).
Furthermore, the bioactivity score of 2-DG derivative (1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose)
suggested that it mainly acts as a GPCR ligand (Bioactivity score GPCR ligand˜ 0.13), ion channel modulator
7
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(Bioactivity scoreIon channel modulator ˜ 0.04) and protease inhibitor (Bioactivity score Protease inhibitor˜ 0.17).
In alliance with the bioactivity analysis, molecular docking data of 2-DG derivative has also suggested it to
be a significant protease inhibitor (E 2-DG derivative + Protease = -187.64 Kcal/mol).
3.6 Toxicity estimation
In silico toxicity estimation of the drug moieties (2-DG and 2-DG derivative) was conducted by using
Toxicity Estimation Software Tool (T.E.S.T) which predicts the key toxicity parameters (Rat acute dose
LD50, bioaccumulation factor, developmental toxicity and Ames mutagenicity) on the basis of the chemical
structure. The fundamental principle behind such toxicological assessment is quantitative structure activity
relationship (QSAR) as generated on the basis of OECD datasets. Computational assessment of these
toxicity parameters also aids in predicting the probable side effects of the test compounds (Barron et al.,
2012). In the present study, the tested ligands (2-deoxy-D-glucose and 1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-
glucopyranose did not show any major signs of toxicity or side effects as shown in Table 5 . In earlier studies
that has been carried out in animals and humans have proved that 2-deoxy-D-glucose and 1, 3, 4, 6-Tetra-
O-acetyl-2-deoxy-D-glucopyranose are safe to be administered by all routes of administration (Mohanti et
al., 1996; Singh et al., 2005; Vijayaraghavan et al., 2006). Moreover, 2-DG has already been tested for its
efficacy as radio-therapeutic and cytotoxic chemotherapeutic targeting pancreatic, breast, ovarian and lung
cancer. However, its short half life and very low bioaccumulation factor limits the utility of 2-DG. Certain
contraindications and adverse drug reactions have also been found to be associated with higher doses of 2-
DG. These complications include fatigue, dizziness, nausea and hypoglycemia. However, in previous studies
conducted on brain tumor patients (glioblastoma), it was observed that most of the side effects of oral
administration of 2-DG (upto doses of 250 mg /kg b.w.) are transient and reversible (Singh et al., 2005).
Additionally, the said contraindications can be surmounted by using 2-DG derivatives as prodrugs. Taking
this into account, tetra-acetate glucopyranose derivative of 2-DG can be used as a prodrug to improve 2-DG’s
pharmacokinetics, bioavailability and its drug-like properties (Pajak et al., 2020).
4. Conclusion
The biggest challenge in battling the novel coronavirus (nCoV-19) pandemic is the dearth of effective thera-
peutic regimens. The presentin silico study was aimed to assess the probable utility of bioactive compounds,
2-deoxy-D-glucose and its derivative 1,3,4,6-Tetra-O-acetyl-2-deoxy-D-glucopyranose against nCoV-19. The
most pertinent viral physiological targets (viral spike glycoprotein S2, viral NSP15 endoribonuclease and
viral main protease 3CLpro) were selected as receptors for conducting molecular docking analysis. The
computer based pharmacophore modeling approach has generated interesting insights into the underlying
binding mechanisms of the above-mentioned viral receptors with 2-DG and 2-DG derivative. It is noteworthy
that 2-deoxy-D-glucose have shown significant activity towards inactivating the SARS-CoV-2 viral recep-
tors, wherein, the E-value of docking of 2-DG with viral main protease 3CLpro and NSP15 endoribonuclease
is significantly better than that of the standard drug lopinavir and favipiravir. Such significant binding
affinities of 2-DG result from formation of a salt bridge between the hydroxyl group of 2-deoxy-D-glucose
and carbonyl residue of Proline (108th position) found in the viral protease. Similarly, 2-DG tetra-acetate
glucopyranose derivative (prodrug of 2-DG) displayed exceptional binding efficiencies while docking with
viral protease, viral endonuclease and spike glycoprotein. The in silico bioactivity analysis suggest that both
these molecules act mainly as protease inhibitors. Present results also indicate that both 2-DG and 2-DG
derivative possess adequate oral bioavailability without any major signs of toxicity or side effects,
In sum, present in silico results, taken together with the published empirical findings on the effects of 2-DG
on retrovirus infected cell lines and murine model systems, suggest that 2-DG may considerably reduce the
infectivity and virulence of nCOVID-19 by inhibiting both the entry and the replication of the virus inside
the host cells. To verify this possibility, further basic studies on model systems infected with nCOVID-19 are
necessary before human clinical trials can be conducted. In view of the huge global devastation caused by the
current viral pandemic and lack of any effective therapy, research work to explore the therapeutic potential
of 2-deoxy-D-glucose and 1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose should be urgently undertaken
with well coordinated multi-institutional collaborations.
8
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Author Contributions
AB, VJ and RKS conceived the presented research. PT, SS and SND analyzed the information, generated
the artwork, and co-wrote the manuscript. RKS and AV investigated and supervised the findings of the
work. VJ and RKS provided critical revision of this article, and approved the manuscript for submission.
All authors agreed with the final version of this manuscript.
Funding
No external funding has been received.
Ethics Statement
The authors confirm that the ethical policies of the journal, as noted on the journal’s author guidelines page,
have been adhered to. No ethical approval was required as this is an in silico study.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relation-
ships that could be construed as a potential conflict of interest.
Acknowledgments
The authors are grateful to Swami Ramdev Ji for institutional research facilities and supports. Authors
gratefully acknowledge the efforts of colleagues of Patanjali Research Institute for their help in data col-
lection and processing. We are also thankful to Mr. Gagan Kumar and Mr. Lalit Mohan for their swift
administrative supports and encouragements.
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Table 1.doc available at https://authorea.com/users/307420/articles/438392-glucose-antimetabolite-
2-deoxy-d-glucose-and-its- derivative-as-promising-candidates-for-tackling-covid- 19-insights-
derived-from-in-silico-docking-and- molecular-simulations
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Table 2.doc available at https://authorea.com/users/307420/articles/438392-glucose-antimetabolite-
2-deoxy-d-glucose-and-its- derivative-as-promising-candidates-for-tackling-covid- 19-insights-
derived-from-in-silico-docking-and- molecular-simulations
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Table 3.doc available at https://authorea.com/users/307420/articles/438392-glucose-antimetabolite-
2-deoxy-d-glucose-and-its- derivative-as-promising-candidates-for-tackling-covid- 19-insights-
derived-from-in-silico-docking-and- molecular-simulations
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Table 4.doc available at https://authorea.com/users/307420/articles/438392-glucose-antimetabolite-
2-deoxy-d-glucose-and-its- derivative-as-promising-candidates-for-tackling-covid- 19-insights-
derived-from-in-silico-docking-and- molecular-simulations
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Table 5.doc available at https://authorea.com/users/307420/articles/438392-glucose-antimetabolite-
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derived-from-in-silico-docking-and- molecular-simulations
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... This molecule contains oxygen donor, in different positions, which causes it to behave as a multidentate ligand [7] . 2-DG can be classified as an antiviral in broad terms, but it is not an antiviral in the true sense since it does not suppress the virus [8] . It only aggregates within the cell, cutting off the growth material needed for the virus to spread. ...
... It only aggregates within the cell, cutting off the growth material needed for the virus to spread. Balkrishna et al. evaluated the glucose antimetabolite 2-DG as well as its derivatives as potential corona virus inhibitors [8] . Dwarakanath investigated enhancing cancer therapy by targeting glucose metabolism utilizing 2-DG [9] . ...
... Medical studies with 2-DG have revealed the difficulties in using it as a monotherapy due to the weak medication properties, prompting investigators to focus on enhancing bioavailability and achieving greater therapeutic concentrations [7][8][9] . New glucose biologics, when coupled with other powerful cytotoxic drugs, might destroy cancer cells in a spontaneous way [13] . ...
Article
Studies of the geometrical, vibration, absorption and physicochemical properties of 2-deoxy-D-glucose with and without metal clusters are reported using the DFT method. 2-Deoxy-D-glucose forms stable clusters with transition metal clusters of copper, silver and gold. Frontier molecular orbitals and molecular electrostatic potential of 2-deoxy-D-glucose and associated metal clusters (Cu6, Au6, Ag6, 2-DGCu6, 2-DGCu5Au, 2-DGCu5Ag, 2-DGAu6, 2-DGAu5Ag, 2-DGAu5Cu, 2 -DGAg6, 2-DGAg5Au, 2-DGAg5Cu) are examined with the B3LYP / LANL2DZ basis set. It is observed that the stability and chemical properties of 2-deoxy-D-glucose strongly depends on the cluster size. The molecular electrostatic potential maps were developed to provide information about the chemical reactivity of the molecules to explain intermolecular interactions. Then, to explore the ligand-protein recognition properties molecular docking and molecular dynamic (MD) simulation analyses have shown that the compound under consideration possesses potential activity as anti-cancer, anti-SARS-CoV-2, anti-SARS-CoV. Each of these analyzes contributes significantly to our understanding of the biological effects of the molecules outlined.
... This molecule contains oxygen donor, in different positions, which causes it to behave as a multidentate ligand [7] . 2-DG can be classified as an antiviral in broad terms, but it is not an antiviral in the true sense since it does not suppress the virus [8] . It only aggregates within the cell, cutting off the growth material needed for the virus to spread. ...
... It only aggregates within the cell, cutting off the growth material needed for the virus to spread. Balkrishna et al. evaluated the glucose antimetabolite 2-DG as well as its derivatives as potential corona virus inhibitors [8] . Dwarakanath investigated enhancing cancer therapy by targeting glucose metabolism utilizing 2-DG [9] . ...
... Medical studies with 2-DG have revealed the difficulties in using it as a monotherapy due to the weak medication properties, prompting investigators to focus on enhancing bioavailability and achieving greater therapeutic concentrations [7][8][9] . New glucose biologics, when coupled with other powerful cytotoxic drugs, might destroy cancer cells in a spontaneous way [13] . ...
Research
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Please cite this article as: P. Vennila, M. Govindaraju, G. Venkatesh, C. Kamal, Molecular structure, vibrational spectral assignments (FT-IR and FT-RAMAN), NMR, NBO, HOMO-LUMO and NLO properties of O-methoxybenzaldehyde based on DFT calculations, Journal of Molecular Structure (2016),
... reprogramming after SARS-COV-2entry to satisfy the increased demand for nutrients and energy for viral replication, where 2-DG, a glucose antimetabolite, might be a promising therapeutic option since it works as a dual inhibitor of glycolysis and glycosylation (Balkrishna et al., 2020). J o u r n a l P r e -p r o o f ...
Article
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Since its inception in late December 2020 in China, novel coronavirus has affected the global socio-economic aspect. Currently, the world is seeking safe and effective treatment measures against COVID-19 to eradicate it. Many established drug molecules are tested against SARS-CoV-2 as a part of drug repurposing where some are proved effective for symptomatic relief while some are ineffective. Drug repurposing is a practical strategy for rapidly developing antiviral agents. Drug repurposing typically begins with virtual screening of existing drugs using docking experiments. Many drugs are presently being repurposed utilizing basic understanding of disease pathogenesis and drug pharmacodynamics, as well as computational methods. In the present situation, drug repositioning could be viewed as a new treatment option for COVID-19. Several new drug molecules and biologics are engineered against SARS-CoV-2 and are under different stages of clinical development. A few biologics drug products are approved by USFDA for emergency use in the covid management. Due to continuous mutation, many of the approved vaccines are not much efficacious to render the individual immune against opportunistic infection of SARS-CoV-2. Hence, there is a strong need for the cogent therapeutic agent for covid management. In this review, a consolidated summary of the therapeutic development against SARS-CoV-2 is depicted along with an overview of effective management of post COVID-19 complications.
... Most of these vaccines are currently in use in different countries. Recently Drug Controller General of India (DCGI) has approved trials of 2-Deoxy-d-glucose (2-DG) medicine introduced by Defence Research and Development Organization (DRDO) (Balakrishna 2020). 2-DG is given to many COVID-19 patients to prevent the use of supplemental oxygen . ...
Article
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The unavailability of a proper drug against SARS-CoV-2 infections and the emergence of various variants created a global crisis. In the present work, we have studied the antiviral behavior of feverfew plant in treating COVID-19. We have reported a systematic in silico study with the antiviral effects of various phytoconstituents Borneol (C10H18O), Camphene (C10H16), Camphor (C10H16O), Alpha-thujene (C10H16), Eugenol (C10H14O), Carvacrol (C10H14O) and Parthenolide (C15H20O3) of feverfew on the viral protein of SARS-CoV-2. Parthenolide shows the best binding affinity with both main protease (Mpro) and papain-like protease (PLpro). The molecular electrostatic potential and Mulliken atomic charges of the Parthenolide molecule shows the high chemical reactivity of the molecule. The docking of Parthenolide with PLpro give score of -8.0 kcal/mol that validates the good binding of Parthenolide molecule with PLpro. This complex was further considered for molecular dynamics simulations. The binding energy of the complex seems to range in between -3.85 to -11.07 kcal/mol that is high enough to validate the stability of the complex. Free energy decomposition analysis have been also performed to understand the contribution of residues that reside into the binding site. Good binding affinity and reactivity response suggested that Parthenolide can be used as a promising drug against the COVID-19. Graphical abstract: Supplementary information: The online version contains supplementary material available at 10.1007/s11696-022-02067-6.
... A prospective randomised study from India did not find any clinical benefit of remdesivir use in terms of mortality reduction in patients with moderate to severe COVID-19 even after adjustment for baseline clinical status. [12,13] The other drugs, which promised a remarkable recovery (hydroxychloroquine, azithromycin, tocilizumab) were later found to be not effective [14] and new drugs such as 2-deoxy-d-glucose (2DG), [15] tofacitinib, [16] baricitinib [17] and pirfenidone [18] are being revisited. 2-deoxy-d-glucose, the latest entrant as an adjuvant, available as an oral sachet developed by the Defence Research and Development Organisation (DRDO), acts on the glycolytic pathway and glycosylation of the viral protein. ...
... 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 [40]. ...
... 2-deoxy-D-glucose (2-DG): A glucose analogue, 2-deoxy-D-glucose, is believed to have profound effects on a range of diseases such as cancer, viral infection and ageing-related morbidity 28 . Recent in vitro studies suggest the potential benefits of using 2-DG to mitigate COVID-19 infection 29,30 . A Phase 2 trial to determine the safety and efficacy of the drug as an adjunctive therapy to standard of care in patients with moderate-to-severe COVID-19 is underway at 12 sites (CTRI/2020/06/025664). ...
Article
Since the beginning of the year, the deadly coronavirus pandemic, better known as coronavirus disease 2019 (COVID-19), brought the entire world to an unprecedented halt. In tandem with the global scenario, researchers in India are actively engaged in the conduct of clinical research to counter the pandemic. This review attempts to provide a comprehensive overview of the COVID-19 research in India including design aspects, through the clinical trials registered in the Clinical Trials Registry - India (CTRI) till June 5, 2020. One hundred and twenty two registered trials on COVID-19 were extracted from the CTRI database. These trials were categorized into modern medicine (n=42), traditional medicine (n=67) and miscellaneous (n=13). Of the 42 modern medicine trials, 28 were on repurposed drugs, used singly (n=24) or in combination (n=4). Of these 28 trials, 23 were to evaluate their therapeutic efficacy in different severities of the disease. There were nine registered trials on cell- and plasma-based therapies, two phytopharmaceutical trials and three vaccine trials. The traditional medicine trials category majorly comprised Ayurveda (n=45), followed by homeopathy (n=14) and others (n=8) from Yoga, Siddha and Unani. Among the traditional medicine category, 31 trials were prophylactic and 36 were therapeutic, mostly conducted on asymptomatic or mild-to-moderate COVID-19 patients. This review would showcase the research being conducted on COVID-19 in the country and highlight the research gaps to steer further studies.
Article
Background: The first case of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral disease in the world was announced on 31st December 2019 in Wuhan, China. Since then, this virus has affected more than 440 million people, and today the world is facing different mutant strains of the virus, leading to increased morbidity rates, fatality rates, and surfacing re-infections. Various therapies, such as prophylactic treatments, repurposed drug treatments, convalescent plasma, and polyclonal antibody therapy have been developed to help combat the coronavirus disease 2019 (COVID-19). Area covered: This review article provides insights into the basic aspects of monoclonal antibodies (mAbs) for the therapy of COVID-19, as well as its advancement in terms of clinical trial and current approval status. Expert opinion: Monoclonal antibodies represents the most effective and viable therapy and/or prophylaxis option against COVID-19, and have shown a reduction of the viral load, as well as lowering hospitalizations and death rates. In different countries, various mAbs are undergoing different phases of clinical trials, with a few of them having entered phases III and IV. Due to the soaring number of cases worldwide, the FDA has given emergency approval for the mAb combinations bamlanivimab with etesevimab and casirivimab with imdevimab.
Article
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Treatment choices for the “severe acute respiratory syndrome‐related coronavirus‐2 (SARS‐CoV‐2)” are inadequate, having no clarity on efficacy and safety profiles. Currently, no established intervention has lowered the mortality rate in the “coronavirus disease 2019 (COVID‐19)” patients. Recently, 2-deoxy-D-glucose (2-DG) has evaluated as a polypharmacological agent for COVID-19 therapy owing to its influence on the glycolytic pathway, interaction with viral proteins, and anti-inflammatory action. In May 2020, the Indian drug regulatory authority approved 2-DG as an emergency adjunct therapy in mild to severe COVID-19 patients. Clinical studies of 2-DG corroborate that it aids in faster recovery of hospitalized patients and decreases supplemental oxygen. Herein, we describe the development process, synthesis, mechanism of viral eradication, and preclinical and clinical development of 2-DG and its derivatives as molecularly targeted therapeutics for COVID-19 treatment.
Preprint
Objective : SARS-CoV-2 causes COVID-19, a life-threatening respiratory illness with high rates of morbidity and mortality. As on date, there is no specific medicine to prevent or treat COVID-19. Therefore, there is an acute need to identify evidence-based holistic and safe mitigators. Methods : The present study is aimed to screen ligands of herbal origin using rationale based bioprospection analysis and subsequently predict their binding potential subdue the major drug targets for novel Coronavirus by employing computer-aided virtual screening. Further, comparative analysis of the binding potential of an approved chemical analogue and selected herbal ligands were also predicted. The selection of receptors was performed based on their pathophysiological relevance, as assessed by a PubMed based keyword hits matrix analysis. The drug likeliness and ADMETox descriptors of 24 herbal ligands were computationally predicted. Docking studies were further conducted with those phytoligands that qualified these parameters. An existing antimalarial drug, hydroxychloroquine, was also docked with all the selected viral receptors and its theoretical binding energy was set up as a standard for comparison as well as scrutinization of binding energies of the phytoligands. Results : The docking studies suggested that the herbal ligand, namely, gamma-glutamyl-S-allylcysteine demonstrated highly significant binding energies with viral spike glycoprotein, endoribonuclease and main protease (binding energy ≥ -490 kcal/mol for all the tested viral receptors). Conclusion : Gamma-glutamyl-S-allylcysteine demonstrated more significant binding potential as compared to the known chemical analogue, i.e. , hydroxychloroquine, as observed in the computational docking studies. This study serves to present pre-eminent information for further clinical studies highlighting the utility of herbal ligands as probable lead molecules for mitigating novel Coronavirus infection.
Article
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Mutation and adaptation have driven the co-evolution of coronaviruses (CoVs) and their hosts, including human beings, for thousands of years. Before 2003, two human CoVs (HCoVs) were known to cause mild illness, such as common cold. The outbreaks of severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) have flipped the coin to reveal how devastating and life-threatening an HCoV infection could be. The emergence of SARS-CoV-2 in central China at the end of 2019 has thrusted CoVs into the spotlight again and surprised us with its high transmissibility but reduced pathogenicity compared to its sister SARS-CoV. HCoV infection is a zoonosis and understanding the zoonotic origins of HCoVs would serve us well. Most HCoVs originated from bats where they are non-pathogenic. The intermediate reservoir hosts of some HCoVs are also known. Identifying the animal hosts has direct implications in the prevention of human diseases. Investigating CoV-host interactions in animals might also derive important insight on CoV pathogenesis in humans. In this review, we present an overview of the existing knowledge about the seven HCoVs, with a focus on the history of their discovery as well as their zoonotic origins and interspecies transmission. Importantly, we compare and contrast the different HCoVs from a perspective of virus evolution and genome recombination. The current CoV disease 2019 (COVID-19) epidemic is discussed in this context. In addition, the requirements for successful host switches and the implications of virus evolution on disease severity are also highlighted.
Article
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World Health Organization has declared the ongoing outbreak of coronavirus disease 2019 (COVID-19) a Public Health Emergency of International Concern. The virus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses. Human infection with SARS-CoV-2 leads to a wide range of clinical manifestations ranging from asymptomatic, mild, moderate to severe. The severe cases present with pneumonia, which can progress to acute respiratory distress syndrome. The outbreak provides an opportunity for real-time tracking of an animal coronavirus that has just crossed species barrier to infect humans. The outcome of SARS-CoV-2 infection is largely determined by virus-host interaction. Here, we review the discovery, zoonotic origin, animal hosts, transmissibility and pathogenicity of SARS-CoV-2 in relation to its interplay with host antiviral defense. A comparison with SARS-CoV, Middle East respiratory syndrome coronavirus, community-acquired human coronaviruses and other pathogenic viruses including human immunodeficiency viruses is made. We summarize current understanding of the induction of a proinflammatory cytokine storm by other highly pathogenic human coronaviruses, their adaptation to humans and their usurpation of the cell death programmes. Important questions concerning the interaction between SARS-CoV-2 and host antiviral defence, including asymptomatic and presymptomatic virus shedding, are also discussed.
Article
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Abstract An acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.
Article
The World Health Organization (WHO) on March 11, 2020, has declared the novel coronavirus (COVID-19) outbreak a global pandemic (1). At a news briefing , WHO Director-General, Dr. Tedros Adhanom Ghebreyesus, noted that over the past 2 weeks, the number of cases outside China increased 13-fold and the number of countries with cases increased threefold. Further increases are expected. He said that the WHO is "deeply concerned both by the alarming levels of spread and severity and by the alarming levels of inaction," and he called on countries to take action now to contain the virus. "We should double down," he said. "We should be more aggressive." [...].
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Since the outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, this disease has spread rapidly around the globe. Considering the potential threat of a pandemic, scientists and physicians have been racing to understand this new virus and the pathophysiology of this disease to uncover possible treatment regimens and discover effective therapeutic agents and vaccines. To support the current research and development, CAS has produced a special report to provide an overview of published scientific information with an emphasis on patents in the CAS content collection. It highlights antiviral strategies involving small molecules and biologics targeting complex molecular interactions involved in coronavirus infection and replication. The drug-repurposing effort documented herein focuses primarily on agents known to be effective against other RNA viruses including SARS-CoV and MERS-CoV. The patent analysis of coronavirus-related biologics includes therapeutic antibodies, cytokines, and nucleic acid-based therapies targeting virus gene expression as well as various types of vaccines. More than 500 patents disclose methodologies of these four biologics with the potential for treating and preventing coronavirus infections, which may be applicable to COVID-19. The information included in this report provides a strong intellectual groundwork for the ongoing development of therapeutic agents and vaccines.
Preprint
The novel coronavirus (2019-nCoV) is a human and animal pathogen recently emerged in the city of Wuhan in Hubei province of China, causing a spectrum of severe respiratory illnesses. Corona viruses makes entry in to human cells through its spike (S) protein that binds to cell surface receptors. Wide spread of 2019-nCoV has been attributed to relatively high affinity of S protein to its receptor. Although S protein is a highly importantdrug target, unavailability of a high-resolution crystal structure and solvent accessible binding surface has made it a tedious target for current rapid virtual screening. A homology model of the receptor binding domain (RBD) of 2019 -n CoV S protein that is reasonably acceptable for drug screening was prepared using a high resolution crystal structure of SARS corona virus (SARS CoV)S protein. Data obtained from RBD- receptor docking experiments and published molecular dynamics experiments were used to map a RBD-receptor interaction hotspot that can be used for designing small molecule inhibitors. The hot spot was then used for virtual screening of more than 3000 drugs approved by U.S Food and Drug Administration (FDA) and other authorities for human use. Two anthracycline class drugs (zorubicin and aclarubicin) and a food dye (E 155) were predicted to be potent inhibitors of RBD – receptor interaction. Results of present study provide evidence for the potential of these compounds asprophylactic medications or for use to reduce disease severity of COVID -19.
Article
Key points: • Novel coronavirus (COVID-19)-infected pneumonia usually manifests as bilateral ground-glass opacities in the lung periphery on chest CT scans. • Role of radiologists includes not only early detection of lung abnormality, but also suggestion of disease severity, potential progression to acute respiratory distress syndrome, and possible bacterial co-infection in hospitalized patients.