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.