Bioinformatics approaches to understand the interactions between the SARS corona Virus (SARS-CoV19) with stranded drugs of anti-retro viral treatment, Influenza and Malaria.

Background: Severe acute respiratory syndrome (SARS) is highly contagious disease caused by virus COVID19. The first case is reported in Wuhan, China, with rapid spreading all over the world and the rate of mortality is also high. SARS-CoV and another human coronavirus, HCoV-NL63 has large spike protein (S) on the virion surface mediates both cell attachment and membrane fusion with receptor sites present on host cell-surface zinc peptidase, angiotensin-converting enzyme 2 (ACE2). Methodology: In the present study, molecular docking studies have been carried out to assess the interaction between the novel corona virus protein COVID19 with stranded drugs used for influenza, anti-retro viral therapy and malaria drugs by using Accelerys discovery studio 2.5, followed by analysis of data. The present study will help to design the drugs against the corona virus and understand the mode of treatment for SARS. Results: All the four-protein receptor of COVID 19 proteins at particular amino acid position binds to the NH and H atom of anti-retro viral therapy drugs (Atazanavir, Doravirine, Emitricitabine, Entravirine, Raltegravir, Tenofavir Disproxil, and Zidovudin) and anti-malaria drug (Hydroxy chloroquine) with less hydrogen bond distance with maximum docking scores which indicates that these compounds can acts against the COVID19 virus. Gene mania network help to design the novel drugs and diagnosis. Conclusions: This is first report to show the molecular docking interaction between the COVID19 protein with stranded drugs of anti -viral treatment. anti-viral drugs Atazanavir, Doravirine, Emitricitabine, Entravirine, Raltegravir, Tenofavir Disproxil, and Zidovudin and malaria drug Hydroxy chloroquine has more strong binding with COVID19 protein receptors.

infections are raised in Wuhan China, spreads to all over the world leading to the lethal deaths(3)2.
According to the WHO report, around 89,000 cases were found to be COVID19 positive in China. In India, according to the report by the Ministry of Health and Family Welfare, the pandemic spread of COVID19 from china to India on 30th January 2020. As of now (23rd march, 2020), the COVID-19 positive cases have reached to 415 and death cases were reported to be 7, after Maharashtra, Kerala, Noida, and Karnataka reported fresh cases (https://www.mohfw.gov.in/). Several studies are confirming that COVID19 infected patients with co-morbidities like has hypertension, diabetes mellitus…. etc have higher rate of death. Study by Qin et al included1099 patients with confirmed COVID-19 positive, of whom 173 had severe disease with comorbidities of hypertension (23·7%), diabetes mellitus (16·2%), coronary heart diseases (5·8%), and cerebrovascular disease (2·3%). The death rate was also found to be very high (12)3. The principle mechanism of coronavirus binds to the host cells is, it has spike (S) glycoproteins that promote the viral entry into host cells (7,10,16,22)4-7. The spike proteins contain two distinctive domains, the C-terminal domain (S1-CTD) and the Nterminal domain (S1-NTD), both of which can plays role as receptor-binding domains (RBDs) (9) 1. S1-CTDs and S1-NTDs from three major coronavirus genera recognize at least four protein receptors and three sugar molecules/ receptors and demonstrate a complex receptor recognition pattern(9, 16)1, 6.
Several studies are demonstrating that SARS-CoV-2 Spike S1 uses angiotensin converting enzyme receptor 2 (ACE2) to enter cells and that the receptor-binding domains of SARS-CoV-2 S1 and SARS-CoV S bind with similar affinities to human ACE2 and transmembrane Serine Protease 2 (TMPRSS2) correlating with the efficient spread of SARSCoV-2 among human epithelial cells i.e. lungs (2, 5, 19-21, 23)8-13. We might think that, after the viral entry into the host cells, virus may be continuously replicate and lysis the host cells, then spreads to the other cells or this RNA virus may block the host metabolic machinery. The SARSCoV-2 Spike glycoprotein harbours a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. Cryo-EM structures of the SARSCoV-2 Spike ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry(16)6. Finally, SARS-CoV S murine polyclonal antibodies potently inhibited SARSCoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved Spike epitopes can be elicited upon vaccination(16)6. Right now, there is no particular treatment for COVID19 positive patients, however doctors are treating the patients with anti-retroviral therapy, swine flu and influenza flu therapy. The antiviral drug, called Favipiravir or Avigan, showed positive response in clinical trials involving 340 individuals in Wuhan and Shenzhen, said by Zhang Xinmin, of China's science and technology ministry (https://www.genengnews.com/news/coronavirus-gileads-remdesivir-begins-trials-as-researcherspublish-positive-in-vitro-results/.) Anti-retro-viral drugs are using for the treatment of HIV positive patients such as nucleoside (lamivudine, zidovudine, didanosine, emtricitabine, tenofovir, stavudine and abacavir) and non-nucleoside (efavirenz, nevirapine, delavirdine, etravirine and rilpivirine) reverse transcriptase inhibitors block the reverse transcription(4)14. Integrase inhibitors block the viral DNA into host DNA by blocking integrase (raltegravir, elvitegravir and dolutegravir) (11,14,15) 15-17 and protease inhibitors(saquinavir, ritonavir, nelfinavir, indinavir and amprenavir) block the viral protease enzyme required for mature virions production(6, 18)18, 19, CCR5 (Chemokine receptor type 5) antagonist, Fusion inhibitor (Enfuvirtide) also block the viral entry into the host(1)20… etc

Methods
In the present study, we have planned to study the molecular docking interaction between viral protein COVID19 and ligands of retroviral and malaria therapeutic drugs.  (Table 1,

2, 3 and 4).
Genemania: It is a free access online tool for predict genes and proteins interaction based on previous literature support (17)[23]. In the present study we will assess the structural analysis of COVID19 and their interaction with other molecules or receptors present on the host cell surface. In the present study the ACE2 and TMPRSS2 proteins interaction with other proteins, co expression of these proteins, shared protein domains, genetic interactions with other genes, colocalization of these genes, genes which are involved in similar pathway is studied by Genemania (17)[23]. This will help to predict the ACE2 and TMPRSS2 proteins interaction with other proteins and it also helps in studying the molecular mechanisms of COVID 19 positive cases because elevated ACE2 and TMPRSS2 proteins are associated with COVID 19 viral entry (Fig 5 and 6). Understanding the molecular mechanism after viral entry will defiantly help in diagnosis (RT-PCR analysis for Co-expression markers) and to the design the novel drugs.

Results
Molecular docking results were identified basis on the ideal interacted ligands were scrutinized based on the greatest ligand binding poses were identified using the low binding energy, high docking score and the number of H-bonding, hydrophobic interactions at receptor site. In the Table.1 Declarations the manuscript.

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Conflicts of interest:
There is no conflict of interest between the authors.