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, 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 Coronaviruses 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), nosocomial 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 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 glycoprotein (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.