COVID-19, an infectious disease caused by Severe Acute Respiratory Syndrome Virus (SARS-CoV-2) has become an unexpected threat to the human population. With the exponential raising of the infection followed increasing mortality rate day by day; the World Health Organization ((WHO)) has reported active cases 14,348,858 and death of 603,691 humans on July 20th, 2020 . The threat has forced a major responsibility to scientiﬁc society in the search for new diagnosis methods, treatment and preventive solutions. Existing repurposed drugs are been neglected by the medical community due to associated side eﬀects .
CoV belongs to the family Coronaviridaewith a large RNA genome of 30 kb, positive-sensed and non-segmented . The virion structure contains four parts of protein which are Spike proteins (S-proteins), Membrane proteins (M-proteins), Envelope proteins (E-proteins) and Nucleocapsid proteins (N-proteins). Of these S-proteins play a major role in transfer of virion particles from the virus to the host cells using ACE2 . Although various literature have highlighted the importance of other protein; the S-protein is currently well studied and has been considered to be as a potent drug target . The S-protein exhibit in homo-trimeric state with N-terminal glycosylation in which the S-polypeptide chain cleaved into two subunit S1 and S2 . The S1 subunit with the larger receptor binding domain and the S2 subunit which induces the membrane fusion polypeptides forming the six helix bundle which results in complete fusion and insertion of viral genome to the host cell cytosol . Hence, structural analysis on the S-protein could reveal possible mechanisms by which the viral replication could be terminated/controlled .
Till date many studies are involved in targeting ACE2 receptor (Angiotensin Converting Enzyme-2), an amino peptidase which found to act as a cellular gateway for the entry of viral RNA into the cells using the S-proteins present in the surface of the virus [5, 8]. But, ACE2 receptor is not only the gateway present on cell membrane to carry this virion into the cells, there are other cellular surface proteins which could also take this role. One such protein is Glucose Regulated Protein 78 (GRP78) reside in lumen of Endoplasmic Reticulum (ER), a heat shock protein with a molecular weight of 78 kDa and a molecular chaperone present in all eukaryotic cells. The major role of GRP78 is protein folding, unfolding and resisting aggregation of proteins in cytosol . The ER-protein when overexpressed escape the KDEL motif receptors which responsible for retention in ER due to its saturation or down regulation and get translocated in the cell membrane and act as Cell Surface GRP78 receptor (CS-GRP78 receptor) which pose the potential threat to our system for viral entry. Hypoxia, glucose starvation and tumor causes ER stress which thus upregulate the GRP78 genes and result in over production of GRP78 . Malfolded protein accumulation also results in overexpression of this protein mostly reported in neurodegenerative disorders and conditions like Alzheimer, Parkinson’s disease and prion protein disease .
CS-GRP78 acts as a multifunctional receptor and binds plenty of proteins and other compounds and activates several pathways which have negative impact on the cells like apoptosis . Several studies reveal that this protein has been responsible for many types of viral entry. In entry of CoxsackieVirus A9 CS-GRP78 involved as the co-receptor along with MHC Class 1 molecule one cell surface . GRP78 studies reported an important host cell factor in the entry of Japanese Encephalitis Virus into the host cells . Studies report that along with Dipeptidyl-peptidase 4 (DPP4), CS-GRP78 involved in the entry of MERS-CoV and reported that introduction of MERS-CoV into cells upregulate the GRP78 genes led to overproduction of GRP78 which both helps in viral entry as well as in virus development . Conditions in which the primary receptor expression in host is low CS-GRP78 act as the main alternate door for the viral entry. Thus inhibiting or reducing CS-GRP78 mediated entry of SARS-CoV-2 is essentially equivalent to inhibiting the ACE2 mediated receptor entry . Protein-protein docking studies established the possible binding site where these two proteins could form complex with good HADDOCK Score, PRODIGY Binding aﬃnity, H-bonds and hydrophobic interaction. It would be a good approach, if we could block the region of S-protein which is responsible for binding to the CS-GRP78 receptor.
Considering the pandemic situation, several health organization and nations in the aim of developing antiviral agents are repurposing drugs like Lopinavir (HIV), Hydroxychloroquinone (Malaria) against COVID [17, 18]. In general, repurposed pose variable target mechanisms and lack eﬀectiveness for coronovirus strain. On the other hand, antiviral drugs also exhibit adverse side eﬀects, which directly and indirectly aﬀect human health . To overcome this shortfall, the development of plant-based drugs and treatment strategies with minimal side-eﬀects are expected . Potentially phytochemicals, which serves as an inﬁnite resource for drug development and novel pharmacophore may be beneﬁted as a therapeutic agent against corona viruses. Their therapeutic applications against diverse viruses can be explained by various antiviral mechanisms such as inhibition of replication process , blocking the binding of virus to the host etc., .
Ancient Indian traditional techniques used several plant parts to treat various infections and disease conditions . Plant parts used in the treatment was experimentally proven to pose eﬀective medicinal properties, further studies on their crude extract and compounds extracted from the plant proved that the extracts are contained with secondary metabolites like alkaloids, ﬂavonoids, phenols, chalcones etc and were termed as phytochemicals. A large number of phytochemicals pose antimicrobial, antiviral and antioxidant properties . These plant parts which were used to treat the disease or infection were later experimentally proven for their medicinal properties . Several literature studies and promising diverse biological assays reveal that a large amount of phytochemicals can be utilized as an eﬀective treatment for retroviral infections. Recently, phytochemicals are used as an inhibitory material for viral infection including HIV, inﬂuenza, common cold etc., [26, 27].
In this study, an attempt has been made to virtually screen potential phytochemicals with high eﬀectiveness particularly from plants originated from Western Ghats, INDIA. Intensive literature survey has been made prior to the screening of phytochemicals. Eﬀectiveness of the screened compounds were validated based on the in-silico docking technique by binding to the S-protein of SARS-CoV-2 and ranked based on the interaction analysis between the protein-receptor complex.