A novel coronavirus designated as SARS-CoV-2 in February 2020 by World Health organization (WHO) was identified as main cause of SARS like pneumonia cases in Wuhan city in Hubei Province of China at the end of 2019. This been recently declared as Global Pandemic by WHO. There is a global emergency to identify potential drugs to treat the SARS-CoV-2. Currently, there is no specific treatment against the new virus. There is a urgency to identifying potential antiviral agents to combat the disease is urgently needed. An effective and quick approach is to test existing antiviral drugs against SARS-CoV-2. Spike protein recognize and bind host receptors like ACE-2 and whose conformational changes facilitates fusion of viral envelop and host membrane leading viral entry into host cells.
Replication of viral RNA occurs through RNA polymerase activity by n unique mechanism. Targeting protease like Spike protein for viral entry and polymerase for replication of virus in host cell can bring effective treatment against novel SARS-CoV-2.
Coronavirus are enveloped with a positive RNA genome. Coronaviridae family of the order Nidovirales, having four genera (α, β, γ and δ). sThe SARS-CoV-2 seems be β genus and probable origin from bat and suspected to have an intermittent host. Structurally coronavirus contain spike (S) protein, envelope (E) protein, membrane (M) protein and nucleocapsid (N) protein. Viral entry through host receptor attachment promoted by spike protein leading to viral fusion to cell membrane of the host and leading to infection. Incubation period may range from 7 days to 21 days with flu like symptoms or sometimes go asymptomatic. Spike protein determines the viral entry and infection. Antiviral therapies targeting human immune system and direct coronavirus are the primary methods of treating the viral infection. Innate immunity of human immune system plays important role as primary defence mechanism against coronavirus infection and its replication. Interferon plays key role in controlling viral replication and immune presentation of viral antigens and to enhance immune responses. Viral entry and replication require human cell signal pathways, by blocking such signal pathways can bring anti-viral effect. Previously known coronavirus infections SARS and MERS causing virus used angiotensin converting enzyme 2 (ACE2) and DPP4 human receptors of human cells independently. Targeting RNA-dependent RNA polymerase (RdRP) of coronavirus is second line of treatment itself include preventing the synthesis of viral RNA through acting on the genetic material of the virus inhibiting virus replication. Activation of the viral spike protein (S) by host cell proteases is essential for viral host cell attachment and entry and the responsible enzymes are potential therapeutic targets. The cellular proteases like furin, cathepsin and receptors like C-type lectins are Ca++-dependent glycan-binding proteins (GBPs) a functional receptor-mediated endocytosis in Golgi bodies plays important role viral infection, replication and maturation as shown in (Figure 1 ). Different strategies for developing drugs and treatment against SARS-CoV-2 include viral protein inhibitors and human cell receptor inhibitors to be studied extensively. Some interferon inhibition like ribavirin and cyclophilin were studied to treat coronavirus pneumonia. Interferon inhibition alone cannot treat the SARS-CoV-2, multi target therapy to be considered as effective way of treating which includes inhibition of receptor proteases like furins, viral proteins like spike (S) and Nsp12, a coronavirus, is an RNA-dependent RNA polymerase (RdRp) protein vital enzyme for coronavirus replication/transcription complex, which can inhibit both viral host cell entry and replication. As designing of novel molecules at present is time consuming and no present therapies existing to treat SARS-CoV-2, we propose use of existing antiviral and other drugs to treat the coronavirus infection. High-throughput screening, bioinformatics and AI based tools and methods to screen existing drug database is the fastest approach to discover drug leads against SARS-CoV-2 for example anti-retro viral drugs like Lopinavir and Ritonavir.
After determining the efficacy, the drugs can be approved through proper hospital based clinical trials for clinical treatment of patients. Viral encoding proteins and human cell proteins aiding viral host cell entry and replication were analysed by bioinformatics tools like Molecular docking and Swiss Dock protocols by conducting homology modelling and ligand preparations. SARS-CoV-2 Viral papain like protease, main protease, spike and RNAdependent RNApolymerase (RdRp) and human furin human ACE2 and type-II transmembrane serine protease proteins were extensively used for targeted drug discovery. Virtual screening of proposed protein targets was docked against anti-HIV and anti-Hepatitis drugs were selected as ligands from drug database including some natural phytochemicals known for antiviral properties. The present study predicts wide range of drug leads that may inhibit this study predicts a variety of compounds that may inhibit novel SARS-CoV-2 coronavirus. Validation of successful drug leads should be studies for complete efficacy using proper in-vitro and in-vivo methods further to continue clinical studies.
Alignment of nucleotide and amino acid sequence analysis-Nucleotide sequence editing was conducted using WebDSV 2.0. Protein alignment was done using Clustalw and protein to DNA sequence comparison done using pairwise alignment EMBL EBI tools [6, 7] . The homology model prediction was carried out through searching in RCSB database included in Fold and Function Assignment System. Prediction Binding pockets was done online dockingserver.com. 3D structure structures are aligned by Autodock and pymol structure alignment tools.
Docking calculations were carried out using Docking Server. Gasteiger partial charges were added to the ligand atoms. Non-polar hydrogen atoms were merged, and rotatable bonds were defined [8] [9] [10] .
Docking calculations were carried out on selected ligands to SARS-CoV-2 main protease PDB ID 6LU7, Human furin PDB ID6HZD, PDB ID 3E9S papain like protease and PDB ID 6NUR Nsp12 of SARS virus. Essential hydrogen atoms, Kollman united atom type charges, and solvation parameters were added with the aid of Autodock tools [11] . Affinity (grid) maps of Å grid points and 0.375 Å spacing were generated using the Autogrid program [11] . Swiss protein modelling and Autodock tools are used for protein clean. Autodock parameter set-and distance-dependent dielectric functions were used in the calculation of the van der Waals and the electrostatic terms, respectively [11] [12] [13] .
Docking simulations were performed using the Lamarckian genetic algorithm (LGA) and the Solis & Wets local search method [12] . Initial position, orientation and torsions of the ligand molecules were set randomly. All rotatable torsions were released during docking. Each docking experiment was derived from 100 different runs that were set to terminate after a maximum of 2500000 energy evaluations. The population size was set to 150. During the search, a translational step of 0.2 Å and quaternion and torsion steps of 5 were applied.
Genetic ID MN908947 SARS-CoV-2 isolate Wuhan-Hu-1, complete genome after BLASTn similarity search had shown more similarity with many bat coronaviruses, some unknown virus and for some synthetic recombinant virus with genetic ID FJ211859.1 see Figure 2 and Figure 3 for whole genome and distance tree analysis. After whole genome alignment in WebDSV 2.0 tools, forward and reverse primers identified as shown in Figure 4 and Figure 5 both circular and linear alignments for 29903 bp.
SMART BLAST analysis shows more than 283 open reading frames shown in supplementary file orf finder-NCBI and in Table 1 orf3a protein of coronaviridae. ORF120 coded for BAT SARS coronavirus HKU3, HKU3-2 and HKU3-9 mainly origin from Rhinolophus affinis an Intermediate horseshoe bat widely available in Asia. ORF238 codes for enzymes dimethylaniline monooxygenase. All positive strand ORF's coded for Bat SARS coronavirus related proteins.
Selected paritaprevir, entecavir, ergotamine tartrate, telaprevir, dihydroergotamine, simeprevir, ergotamine alkaloid, telmisartan, ritonavir tartrate, fgi 106, corosolic acid, chloroquine, darunavir, nelfinavir, glycyrrhizic acid, baicalin, ritonavir, quilajja saponin, lopinavir, amprenavir, fosamprenavir, quercetin, remdesivir, pemetrexed, raltitrexed, sofosbuvir were docked against proteins SARS-CoV-2 main protease PDB ID 6LU7, Human furinPDB ID6HZD, PDB ID 3E9S papain like protease and PDB ID 6NUR Nsp12 (RdRp) in selective manner as mentioned in (Tables 2, 3 and 4) .
Paritaprevir, chloroquine and ritonavir had shown strong multi target inhibition like spike proteins, proteases and furin. Natural compounds like baicalin, corosolic acid had shown multi target inhibition properties against spike proteins, proteases and furin.
At present world is facing pandemic situation because of SARS-CoV-2 infection. There is an urgency to address this situation as no present treatment protocols are not been established.
The only way to develop quick treatment protocols can be achieved by studying detailed case studies of SARS infections caused by influenza and non-influenza viruses and also studying existing antiviral drugs.
Computational and high throughput screening tools are the best aids to design and study the efficacy of existing antiviral drugs along with some anti-inflammatory drugs against SARS-CoV-2 targeted sites. Antiviral drugs like oseltamivir used against neuraminidase of SARS in last decade, favilavir an RNA-Dependent RNA polymerase (RdRp) inhibitor also showed effective against the SARS influenza virus. Recently Japan also proposed use of favipiravir and Avian flu drug to treat SARS-CoV-2 infection. Remdesivir a proposed drug to treat Ebola virus also been proposed to test against SARS-CoV-2. DNA and RNA inhibitors like sofosbuvir and anti-HIV drug compositions also been proposed at present to treat the present global pandemic caused by novel coronavirus. Most of the proposed drugs had shown either less efficacy or effective in some patients but not achieved complete success. In order to develop complete treatment protocol, one should understand the disease pathogenesis. As per case reports available study indicates respiratory outburst due to various inflammatory study indicates severe diarrhoea and respiratory outburst due to inflammatory factors causing death among novel coronavirus infected patients. As per our study we found CD4+ activation leading to TH1 and TH2 cytokines outburst in excessive leading to severe respiratory illness in patients affected by SARS-CoV-2. This virus has Orf zone indicating C lectin type binding receptors of host ( Figure 4 , 5 and 6) which may make this virus to escape MHC Class I antigen presentation leading to asymptomatic conditions in some patients.
Interleukins like IL6, IL8 and IL2 along with TNFα might be main causative inflammatory leading respiratory failure. Based on available case study by [14] most of the patients admitted had shown difficulty in breathing, cough and fever with severe respiratory illness and pneumonia. In this study we propose use of multi target therapy which includes viral protein targets involving in host cell entry and replication and host cytokines. Viral proteins like spike, neuraminidase, main protease (3CLpro), papain like protease (PLpro) and RNA-Dependent RNA polymerase (RdRp) are the key viral protein targets [2] . Inhibition of spike (S) protein binding to ACE 2 will be key prophylactic drug discovery to control SARS-CoV-2.
The present used carried out using computational and high throughput screening tools in order to evaluate the whole Genome analysis of SARS-CoV-2 and identifying potential drugs to treat novel coronavirus influenza. Gene sequence was obtained from NCBI genome database [15, 3] and Molbiol and other BLAST analysis tools were used to analyse genome wide study. Similarity search analysis had shown possible close species relation with BAT SARS Corona virus particularly from Intermediate horseshoe bat (Rhinolophus affinis) and some Beta Coronaviridae family. The data also suggest some possible cross species interaction of Delta coronavirus families and species jump from bats to intermediate host which is unknown or from porcine origin. VISTA Tools for Comparative Genomics had shown some phylogenetic origin of SARS-CoV-2 by chimeric recombination between HKU2 alpha Coronaviridae which caused severe Swine diarrhoea syndrome caused by Bat droppings and HKU15 a delta corona virus causing swine respiratory syndrome (Figure 7) . Some genome wide analysis also matches with Recombination Clone of SARS Coronavirus with genetic ID FJ211859.1 which should be properly evaluated as future indication. Orf reading had shown more than main 238 Orf sites SARS coronavirus Orf3/3a ( Figure 6 ) which is a characteristic protein for SARS Coronavirus family. Some other proteins include NS3/E, small non-structural proteins, well conserved among Coronavirus strains and a small uncharacteristic protein SARS_NS6 with small amino acid sequence. Drugs selected from zinc database like remdesivir, paritaprevir, sofosbuvir, ritonavir, lopinavir, chloroquine derivatives like hydroxychloroquine including natural molecules like glycyrrhizin, corosolic acid and baicalin were used as ligands in docking studies against viral proteins like spike, main protease (3CLpro). Papain like protease (PLpro), RNA dependent RNA polymerase. Docking results had shown paritaprevir, ritonavir and chloroquine derivatives as best drug leads against spike and proteases of SARS-Co-V2. Natural drugs like glycyrrhizin, corosolic acid and baicalin also shown strong binding affinity against spike and protease proteins of novel corona virus. From existing clinical data, we also propose use of anti-inflammatory drugs in treating the SARS-CoV-2 disease progression. In this study we propose for clinical study by combined use of paritaprevir, entecavir, ritonavir, and hydroxychloroquine along with anti-inflammatory drugs and also use of niacinamide, vitamin C, zinc supplements for possible good clinical outcome. We also propose study plant protease inhibitors (PI's), glycoprotein-based antibodies and small molecules like Lysozyme hydrochloride, Oxamniquine and Nateglinide therapies. VISTA GENOME TOOL COMPRATIVE ANALYSIS-JQ065043. Identified potential drug leads against protease and replication polymerase novel corona virus targets.
Drug name