key: cord-0694144-pr698jau authors: Khursheed, Aadil; Jain, Vikrant; Rasool, Ajaz; Rather, Manzoor A.; Malik, Nisar Ahmad; Shalla, Aabid Hussain title: Molecular scaffolds from mother nature as possible lead compounds in drug design and discovery against coronaviruses: A landscape analysis of published literature and molecular docking studies date: 2021-05-11 journal: Microb Pathog DOI: 10.1016/j.micpath.2021.104933 sha: 33da74be6ae99e9aec00da34bc90341402f6d1ae doc_id: 694144 cord_uid: pr698jau The recent outbreak of viral infection and its transmission has highlighted the importance of its slowdown for the safeguard of public health, globally. The identification of novel drugs and efficient therapies against these infectious viruses is need of the hour. The eruption of COVID-19 is caused by a novel acute respiratory syndrome virus SARS-CoV-2 which has taken the whole world by storm as it has transformed into a global pandemic. This lethal syndrome is a global health threat to general public which has already affected millions of people. Despite the development of some potential vaccines and repurposed drugs by some Pharma companies, this health emergency needs more attention due to the less efficacy of these vaccines coupled with the emergence of novel and resistant strains of SARS-CoV-2. Due to enormous structural diversity and biological applications, natural products are considered as a wonderful source of drugs for such diseases. Natural product based drugs constitute a substantial proportion of the pharmaceutical market particularly in the therapeutic areas of infectious diseases and oncology. The naturally occurring bioactive antiviral phytochemicals including alkaloids, flavonoids and peptides have been subjected to virtual screening against COVID-19. Since there is no specific medicine available for the treatment of Covid-19, designing new drugs using in silico methods plays an all important role to find that magic bullet which can target this lethal virus. The in silico method is not only quick but economical also when compared to the other conventional methods which are hit and trial methods. Based on this in silico approach, various natural products have been recently identified which might have a potential to inhibit COVID-19 outbreak. These natural products have been shown by these docking studies to interact with the spike protein of the novel coronavirus. This spike protein has been shown to bind to a transmembrane protein called Angiotensin converting enzyme 2 (ACE2), this protein acts as a receptor for the viral spike protein. This comprehensive review article anticipates providing a summary of the authentic and peer reviewed published literature about the potential of natural metabolites that can be developed into possible lead compounds against this new threat of Covid-19. Main focus of the article will be to highlight natural sources of potential anti-coronavirus molecules, mechanism of action, docking studies and the target proteins as well as their toxicity profiles. This review article intends to provide a starting point for the research endeavors that are needed for the design and development of drugs based on pure natural products, their synthetic or semi-synthetic derivatives and standardized plant extracts. This review article will be highly helpful for scientists who are working or intend to work on antiviral drugs from natural sources. Coronaviruses (CoV's) are RNA enveloped family of viruses mostly found in mammals and birds (Singhal, 2020) . The virus infection causes fetal respiratory or enteric disorders and in rare cases hosts develop neurological and liver disorders (Zubair et al. 2020) . Species-specific effects of CoV's are observed in hosts like some may cause acute or persistent infections. These viruses are highly communicable and transmission may occur through different modes including respiratory and fecal-oral routes. CoV's show distinctive characteristic features in comparison to other viruses like a large genome size even bigger than those viruses having segmented genome (Brian and Baric, 2005) . This huge genome size contributes to wealthy and high variety of genetic expressions shown by CoV's and most importantly these expressions are yet to be fully explored and understood. In the year of 1960, CoV's were assembled under a variant class of by okaviruses (belonging to the family of Roniviridae, okaviruses are large invertebrate nidoviruses) (Sola et al. 2015) . The replication mechanism in CoV's has been investigated in detail, whereas there is limited data on replication of toroviruses and bafiniviruses, this may be of similar replication mechanism followed by these. Virions enter into the target host cell via surface receptors and their spikes (Table 1) . These virions discharge their genome into host cell by fusion of plasma membrane or endocytic vesicles with viral envelope (Yamamoto et al. 2016) . The complete replication procedure operates within cytoplasm of host cell. It involves the formation of sub-genome sized and full-length minus-strand RNA intermediates with the viral genome serving as both mRNA for template for minus-strand synthesis and replicase polyproteins (Zhao et al. 2007 ). Repilication-transcription complex (poorly characterized) catalyzes the RNA synthesis, comprising of host and viral proteins associated with interconnected modified network of double and intracellular membrane vesicles. These vesicles are ostensibly derived of endoplasmic reticulum (De Wilde et al. 2017; Fung and Liu, 2014; Snijder et al. 2020 ). In addition to this all coronoviridae members share the following characteristics; i. Genome: positive sense RNA, unimolecular, linear, infectious, capped, polyadenylated, 26-32 kb in length, and polycistronic morphology. ii. General genomic organization: 5'-UTR-replicase-S-M-N-UTR-3' (genes according to product), with the genome functioning as mRNA for the replicase gene. iii. Replicase gene: it constitutes of overlapping ORFs (1a and 1b) that code for the production of giant polyproteins (pp1a and pp1ab), these giant proteins are generated autoproteolytically and generation of pp1ab needs programmed 21 ribosomal frame shift. J o u r n a l P r e -p r o o f iv. ORFs downstream of the replicase gene: expression from a 3' co-terminal nested set of two or more subgenomic mRNAs that are capped and polyadenylated. v. Morphogenesis: virion assembly through budding of preformed nucleocapsids at smooth intracellular membranes of endoplasmic reticulum/early Golgi compartments. coronavirus originated from bats, spread to raccoon dogs, Chinese ferret badgers and Himalayan palm civets at Guangdong wet markets, China (Hassanin et al. 2020 ). Later the virus moved into human population via consumption or handling of these infected species. Although, SARS was believed to be vanished till the latest casualties done by SARS-CoV-2, the episode highlighted the pathogenic potency of CoV's and their probability to emerge as novel coronavirus infections through transmission among cross-species. Various similar episodes were observed thereafter though they imposed miniscule epidemiological outcomes like OC43 human coronavirus (cattle to humans, through single cross transmission of bovine coronavirus), 229E human coronavirus (bats origin?) and canine respiratory coronavirus (bovine coronavirus transmission to dogs) (Ghosh and Malik, 2020) . The SARS epidemic has enhanced the research interest in the field of CoV's. Virus discovery and molecular surveillance have found nearly 60 novel CoV's, out of which two effect human respiratory system including HCoV-NL63 and HCoV-HKU1 (Cui et al. 2011 ). The farmer is key agent of causing bronchiolitis and croup among children. Additionally, these studies showed novel lineage of mostly avian viruses including Munia, Bulbul and Thrush coronavirus with close relatives possibly found in mammals like Chinese ferret badger and Asian leopard cat (Miłek and Blicharz-Domańska, 2018) . These novel avian viruses were placed under a different genius (Delta-CoV's) on the basis of rooted phylogeny ( Figure 1 ). Bats are exceptionally rich harbors of variety of coronaviruses and hence play a key role in coronavirus evolution and ecology (Wang et al. 2019) . It has been reported that bats may be the original hosts from which lineages for most of the alpha-CoV's and Beta-CoV's were derived. The habitual features of bats like roosting, migration and population densities favor their virus carrier role (Calisher et al. 2006) . This hypothesis has its merits and in recent studies of virus discovery this hypothesis remained truly Herculean proportions. The actual sampling size of the CoV's is J o u r n a l P r e -p r o o f limited though the efforts are primarily concentrated on bats, all of our current insights may be biased. The ongoing lethal pandemic of COVID-19, primarily caused by coronavirus SARSCoV-2, originated from Chinese city of Wuhan, in December 2019 (Velavan and Meyer, 2020 Table 2 ; America tops the list followed by Brazil and India ( Figure 3 ). SARSCoV-2 has a minimum incubation period of two weeks or may be longer in some cases. In early stages SARSCoV-2 mostly may remain asymptotic and can cause multiple infections in some patients before becoming apparent (Arun et al. 2020) . The organs adversely affected by SARS-CoV-2 include lungs, kidneys, heart, liver and genitals (Xie et al. 2020 (Phua et al. 2020) . Moreover, the SARS-CoV-2 has been detected in tears, saliva, urine, and gastrointestinal tract of patients (Mohseni et al. 2020) . The diagnosis of a 72 h child positive with COVID-19 has enhanced the possibility of vertical transmission from mother to fetus. Therefore, much higher precautions and preventive measures should be adopted by the medical staff inside hospitals and ICU's as well. Till date, the mechanism of pathogenesis of SARS-CoV-2 is uncertain and unknown. It is believed that the ACE2 receptor present in alveolar epithelial cells provides passage to the virus by binding to its spike protein via S protein (Li et al. 2005a; Luan et al. 2020) . Once bound to these epithelial cells strong immune responses and direct toxicity gets induced. The resultant inflammation leads to strong cytokine storm generating lethal lung injury which causes lung collapse and ultimately death (Hu et al. 2021) . Pathological studies have demonstrated that SARS-CoV-2 patients develop hyaline membrane and possess diffused alveolar damage. The rest of the features resemble to that of MERS and SARS (Tahir et al. 2020a) . ACE2 is also found in epithelial cells of different organs including intestines, heart, and kidneys. Therefore, once SARS-CoV-2 infection develops it can invade to multi-organs and cause multi-organ failure. Tumor necrosis factor, macrophage inflammatory protein 1α, monocyte chemo-attractant protein-1, interferon gamma-induced protein 10 and levels of IL-2, -6, -7 and -10 granulocyte J o u r n a l P r e -p r o o f colony-stimulation factor, all are found highly elevated in case of severe infection and are considered accountable for poor outcomes (Ragab et al. 2020) . In some patients enhancement in pro-inflammatory CCR4+CCR6+Th17 cells and over activation of lymphocytes promote the immune-mediated injury resulting in transformation of mild infection to severe (Costela-Ruiz et al. 2020) . Predominantly, individuals with reduced immunity and comorbidities are more vulnerable to this infection. Based on recent investigations and data collected from ICU's, COVID-19 patients develop hypoxemia and/or dyspnea within one week of disease onset. Patients with higher viral loads develop even serious complications including acute respiratory distress syndrome, multiple organ dysfunction syndrome, coagulation disorder, metabolic acidosis and septic shock (Weissleder et al. 2020) . Patients with SARS-CoV-2 infection may develop cerebral congestion, edema and neuropathy; attention should be paid to neurological symptoms in clinical practice. Some patients have been reported of initial neurological symptoms including myalgia, impaired consciousness, anosmia, headache, and acute cerebrovascular distortion. In future studies, these neurological complexities and their therapeutic modalities should be elucidated. Secondary SARS-CoV-2 infection markers include downregulation of peripheral blood lymphocytes, amplification of blood inflammatory agents like C-reactive protein and IL-6, amplified lactic acid levels and scanning results predicting multilobar or bilateral infiltration, short-term lesions and pleural effusion (Ponti et al. 2020) . Stimulatingly, some researchers found that the neutrophil-to-lymphocyte ratio (NLR) is an impelling factor that can be used for initial identification of the prognosis of patients with severe COVID-19. Lastly, it should be pointed out that chest CT plays particularly a decisive role in COVID-19 diagnosis and the disease severity J o u r n a l P r e -p r o o f assessment. Chest CT has high diagnostic value in patients who have negative Reverse Transcription-Polymerase Chain Reaction (RT-PCR) results but whose clinical symptoms, auxiliary test results, and epidemiological history make them highly suspected patients (Ai et al. 2020 ). Polymerase chain reaction (PCR) method is considered as the gold standard for disease diagnostics; however, it requires expensive equipment and knowledgeable manpower. Natural products are a rich and valuable gift of Mother Nature to human and other beings on this planet (Khursheed and Jain, 2020) . Since time immemorial, natural products, their derivate and their synthetic analogs have been used to overcome many human ailments including viral infections, ranging from mild to severe. Herbal medicine possesses an enormous scope in nutraceutical market. Most interestingly, the availability, acceptability and rich biological properties have diverted the interest of researchers from synthetic to nature (Khursheed et al. 2016) . Nigella sativa has been reported with substantial suppressive effects against the hepatitis Artemisia annua SARS-CoV 10−1-10−4 mg/mL Unknown 34.5 ± 2.6 μg/mL 9. Lycoris radiata SARS-CoV 10−1-10−4 mg/mL Unknown 2.4 ± 0.2 μg/mL Torreya nucifera-a medicinal plant, is a rich source of flavones and biflavones (Siddiqui et al. 2020 ). These compounds showed potential antiviral activity against SARS-CoV. Out of these compounds, Quercetin, luteolin, apigenin and amentoflavone presented an IC 50 value of 23.8, 20.2, 280.8 and 8.3 µM. Three alkaloids including cepharanthine, fangchinoline and tetrandrine, in a recent investigation were shown with inhibitory effects against early stage death stimulated in HCoV-OC43-infected human lung MRC-5 cells with IC 50 values of 0.83, 1.01 and 0.33 µM, respectively (Refaey and Fayed, 2020) . The antiviral potency of natural products has inspired many researchers, 221 phytochemicals belonging to different classes were investigated for antiviral propensity against SARS-CoV's (Wen et al. 2007 ). Out of 221, curcumin, five lignans, two triterpenes, two sesquiterpenes and ten diterpenes revealed anti-SARS-CoV activity. Further, savinin lignin and 8b-hydroxyabieta-9(11),-13-dien-12-one diterpenoid were reported with inhibitory effects on 3CLpro activity in SARS-CoV with SI of greated than 667 (Wen et al. 2007 ). Betulinic acid imposed inhibition of 3CLpro activity and was competitive to savinin J o u r n a l P r e -p r o o f against SARS-CoV with Ki value 8.2 µM and 9.1 µM, respectively (Wen et al. 2007 (Park et al. 2017 ). Out of these compounds highest inhibition was exerted by papyriflavonol A with an IC 50 of 3.7 µM. Streptomyces hygroscopicus is rich in hygromycin and showed anti-replicative effects in necrotic liver foci and MHV-A59 (mouse hepatitis virus) in a concentration-reliant fashion (Macintyre et al. 1991) . Bacterium Streptomyces parvulus antibiotic, actinomycin D suppressed the penetration and attachment of CoV's into host cell. Likewise, ginsenoside Rb1 one of the active members of ginsenosides isolated from Panax ginseng showed remarkable antiviral activity (Song et al. 2014 ). NIH clinical collection investigated 727 compounds for antiviral activities against human and murine CoV's, the most active compound showing promising activity was recorded to be macetaxine alkaloid (Fielding et al. 2020) . Tylophora indica is rich in alkaloid content and two alkaloids; 7-methoxycryptopleurine and tylophorine, showed potential inhibition of both S and N protein activity and also inhibited the replication of enteropathogenic coronavirus transmissible On the other hand, quercetin, quercetrin, rutin, cinanserin (1 and 2 dpi) isolated from Houttuynia cordata were found to act against murine CoV at 15.63-500 μg/mL. (Vrijsen et al. 1986; Sayed et al. 2020; Chiow et al. 2016) Furthermore, 3β,12-diacetoxyabieta-6,8,11,13-tetraene, 8β-hydroxyabieta-9(11),-13-dien-12one, ferruginol, betulinic acid, curcumin, savinin, and hinokinin inhibited the replication of SARS-CoV (Khare et al. 2020 ). On the other hand, viral yields as well as viral titers were diminished by ouabain molecule and also declined the viral RNA copies in number. Similarly, the laboratory derivatives; 1-(4,5-dihydroxy-3-hydroxymethylcyclopenten-2-enyl)-1H-1,2,3triazole-4 carboxylic acid amide, 1-(4,5-dihydroxy-3-hydroxymethylcyclopenten-2-enyl)-1Himidazole-4-carboxylic acid amide, and 1-(4,5-dihydroxy-3-hydroxymethylcyclopenten-2-J o u r n a l P r e -p r o o f enyl)-1H-1,2,4-triazole-3-carboxylic acid amide revealed remarkable anti-SARS-CoV potential (Cho et al. 2006) . Tylophora indica isolated 7-methoxycryptopleurine and tylophorine showed evident inhibition of replication against CoV-infected swine testicular cells (Mohapatra et al. 2021) . In this study, 7-methoxycryptopleurine (IC 50 : 20 µM) was extra operative than the tylophorine (IC50: 58 µM). In another study, tylophorine was also found to target viral RNA replication and cellular JAK2-mediated dominant NF-κB activation in CoV at 0-1000 µM (Yang et al. 2017) . Structure of some of the important antiviral leads from plants against coronaviruses have been listed in Table 4 . Infectious diseases from time to time have caused serious damages to humanity throughout the world. Viruses are one of the serious agents posing infectious diseases in human beings and have attained resistance to prophylaxis or therapy long before any form of life mainly due to their sole dependence upon the host cells they infect and depend upon for survival and replication. This property of theirs has caused serious issues in drug development and chemotherapy. There are only a handful of antiviral agents available to act upon these infectious diseases caused by viruses included natural product based acyclovir. In order to overcome viruses causing devastating and serious health damages to not only humans but insects, animals, plants, bacteria J o u r n a l P r e -p r o o f and fungi as well, world is turning towards natural products for antiviral leads sue to diversity in structure and bioactivities. Although the search for naturally occurring products which can interfere with viral infections began with the successful isolation of antibiotics from microorganisms but it has not been as intensive as that of synthetic antiviral agents (Vanden Berghe et al., 1986) . This is mainly due to the tendency of most virologists who adopt a rational design of antiviral agents rather than toward empiricism especially with the progress in The development of natural products based drugs against a specific health disorder is more rapid than to develop a potential vaccine. Still, it remains a vertical task due to the enormous structural and chemical varieties of natural metabolites, their chemical extraction and complexity. To save the time involved in natural products research, virtual screening proves to be advantageous for phytochemical screening of natural products and their extracts. This virtual screening is termed as in silico analysis via molecular docking. Since the appearance of COVID-19 as a global pandemic, natural products were subjected to molecular docking to check their role against it. Independent of the class, natural products like steroids, terpenes, quinones, fatty acids, alkaloids, flavonols and flavones revealed similar docking score or binding energy, to that of repurposed J o u r n a l P r e -p r o o f drugs like chloroquine and remdesivir, with replicative proteins is SARS-CoV-2 ( Figure 6) including TMPRSS2, 3CLpro and ACE2 (Hoffmann et al. 2020; Coban et al. 2020 ). More emphasis was laid on ACE2 inhibitors as a probable consequence of primary binding concerning COVID-19 replication. Some of the natural products subjected to virtual screening against ACE2 and 3CL Pro docking targets are listed in table 5 and 6. Epicatechin-(4β,8)-epicatechin-(4β,6)catechin -8.20 (Joshi et al. 2020) Epicatechin-4-epigallocatechin -7.20 (Joshi et al. 2020) Quercetin 3-glucosyl-(1,4)-rhamnoside -6.50 (Joshi et al. 2020) Lactucopicrin 15 Imperialine-3-β-D-glucoside -7.1 (Cheng et al. 2020) J o u r n a l P r e -p r o o f extensively used to treat asthma, cough, fever and diarrhea in Ayurvedic system of medicine; these are the most prevalent symptoms in SARS-CoV-2 infection (Biswas et al. 2002) . Under viral attack, Neem intake amplifies cell and humoral mediated immune responses. Thus, multidimensional antiviral therapeutic potency of Neem led to hypothesizing its possible implications on COVID-19 along with the modern system of medicine. It is believed that Neem may prove a leading natural agent against COVID-19 but requires translational experimentation and a series of experimental database that can support its activity. India is putting all its efforts to design and discover natural products against SARS-CoV-2. and we hope that it is successful". Glycyrrhiza glabra (licorice) may be involved to neutralize the activeness of SARS-CoV-2 due to the presence of active constituents like liquiritin, isoliquiritin, glycyrrhetic acid and glycyrrhizin (Bailly and Vergoten, 2020 ). An investigation regarding the involvement of natural products against COVID-19 has reported that plant extracted components target -OH (hydroxyl) groups of active components in virus thereby deactivating them through esterification. Tea tree (Camellia sinensis) Chinese flowering ash (Fraxinus sieboldiana) Calceolarioside B Indian gooseberry (Phyllanthus emblica) Coronaviruses (CoVs) are a large and diverse family of enveloped and single stranded RNA viruses. This exhibit broad host ranges and infect many mammalian and avian species causing gastrointestinal, upper respiratory, hepatic and central nervous system diseases (Holmes, 2001) . Coronaviruses exhibit a complex pattern for receptor recognition (Li 2015) . The alpha coronavirus HCoV-NL63 and beta coronavirus SARS-CoV both identify a zinc peptidase angotensin converting enzyme 2 (ACE2) (Li et al. 2003; Hofmann et al. 2005) . Other alphacoronavirus such as TGEV, PEDV and PRCV recognize aminopeptidase N (APN0 (Delmas et al. 1992; Liu et al. 2015; Li et al . 2007; Delmas et al. 1993 ). MERS-CoV and HKU4 recognize a serine peptidase, dipeptidase 4 (DPP4) Yang et al. 2014 ). Similarily, MHV recognizes a cell adhesion molecule, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (Dveksler et al. 1991; Williams et al. 1991) . BCoV and OC43 J o u r n a l P r e -p r o o f recognize sugar (Schultze et al. 1991 ). In addition, alpha coronaviruse TGEV and PDEV and gamma coronavirus IBV also use sugar as receptors or coreceptors (Liu et al. 2015; Schultze et al. 1992, Cavanagh and Davis 1986; Schwegmann-Wessels and Herrler 2006; Krempl et al. 1997 ). Besides their role in viral attachment, these receptors have their own physiological functions Mina-Osorio 2008; Boehm and Nabel 2002; Kameoka et al. 1993; Wesley 2005; Hammarstrom 1999; Dove 2001) . Receptor diversity is an exceptional feature of coronaviruses. Subunit S1 of coronavirus consists of two domains, N-terminal domain (S1-NTD) and C-terminal domain (S1-CTD), have been identified with one or both of them potentially functioning as receptor binding domains (RBD). S1-NTDs binds sugar (Liu et al 2015; Li et al 2007; Peng et al. 2012; Promkuntod 2015) with beta coronavirus MHV S1-NTD as only exception that recognizes protein receptor CEACAM1 (Kubo et al. 1994 ). S1-CTDs recognize protein receptors like ACE2,DPP$ and APN (Liu et al. 2015; Wong et al. 2004; Lin et al. 2008; Hofmann et al. 2006; Godet et al. 1994; Du et al. 2013; Mou et al. 2013) . Crystal structures of S1 domains along with functional studies have revealed many interesting features about receptor recognition by coronaviruses (Li 2016 ). SARS-CoV 2 and SARS-CoV both encode large (1253aa;1273 aa) spike protein (Morse et al. 2020) . Sequence identity has revealed 76% identity of spike protein between these two origins with large variation at N terminus. For SARS-CoV there is receptor binding domain in the S1 region interacting with ACE2 with high affinity. For SARS-CoV2, it has also come to the fore that it uses S1 RBD to bind ACE2 for entering human host cells. There is 73.5% sequence identity in RBD regions for these two viruses. Nevertheless, many non-conserved mutations have accumulated in two structural regions interacting directly with ACE2 (Li et al. 2005c ). Crystal and cryo-EM structures of SARS-CoV spike-ACE2 complex have revealed that regions 1 and 2 J o u r n a l P r e -p r o o f engage in hydrophobic interactions and hydrogen bonding with ACE2. Surprisingly, some residues in these regions have been replaced in SARS-CoV2, which eventually will lead loss of some of these interactions. Besides, SARS-CoV2 RBD has been predicted to be weekly interacting with ACE2 as compared to SARS-CoV (Dong et al. 2020) . In case of S2 region, there is no similarity in sequence between these two virus origins. After virus entry, genomic RNA attaches to the host ribosome and translates two large coterminal polyproteins, which are further processed by proteolysis for packaging into new virions (Baranov et al. 2005) . Coronavirus main proteinase (3CLpro) and the papain-like protease (PLpro) are main proteases that participate in proteolysis process (Ziebuhr et al 2000) . Furthermore, for replication of RNA, CoV encodes RNA dependent RNA polymerase RdRp), a replicase (Xu et al. 2003) . As these four proteins viz., Spike, CLpro, PLpro and RdRp, are key for pathogenesis of coronaviruses, therefore, therapeutics currently target them for treatment of SARS-CoV2. Owing to its role in receptor binding and membrane fusion, spike protein of SARS-CoV is an ideal target for vaccine and antiviral development ( However, as of now no established antiviral therapies or preventive vaccines are available for its treatment (Sohrabi et al., 2020) . RdRp with large and deep groove as an active site for RNA polymerization, shows variation at distal site of this active region for SARS-CoV2 as compared to SARS-CoV (Kirchdoerfer and Ward 2019) . High sequence conservation between two enzymes makes it likely targeted with equal efficacy and potency by potent agents developed for SARS-CoV RdRp. Aurintricarboxylic acid (ATA) was one such compound with antiviral activity which targets RdRp. It is an anionic polymer which binds to protein targets and has been demonstrated to prevent replication (Gonzalez et al. 1979; Cushman et al. 1991; He et al. 2004b ). But, despite computational models authorized against known ATA targets, predicting RdRp as bound target, no experimental evidence has demonstrated this relationship (Yap et al. 2005) . Several synthetic compounds including hydroxychloroquine and chloroquine (Cortegiani et al., 2020; Gao et al., 2020) , phosphate have been occasionally used. Antiviral medications such as J o u r n a l P r e -p r o o f remdesiver (Holshue et al., 2020; Wang et al., 2020b) , lopinavir (Yao et al., 2020) and arbidol (Khamitov et al., 2008) have shown promising results. Nucleoside analogues, peptide EK1 and neuraminidase inhibitors are some other treatments explored for controlling pandemic (Lu, 2020) . Purified natural products and traditional herbal medicines have also been surveyed and explored for developing novel antiviral drugs. 83 compounds were screened in Chinese traditional medicines against RdRp of SARS-CoV 2 (Lung et al. 2020 (Petersen et al., 2006) , hence with more testing, they may prove more promising classes of naturally derived compound(s) for the treatment of SARSCoV-2 and other coronavirus infections. Silvestrol, which is a phytochemical from Aglaia sp., was found potent inhibitor A big challenge is to find efficient drug candidates that can overcome infectious diseases with lower or no side-effects. Besides advancements that are being made towards the drug development for many diseases like HIV, AIDS, malaria and cancer, these drugs still cause unwanted side-effects to huge human population globally. Presently, it will be a viable methodology to turn back to "Nature" for answers because of their rich track record in the past. The natural products like taxol, vinblastine, quinine and artemisinin are well established drugs now used in the treatment of cancer and malaria. To address global health issues, the research and drug development concerning natural products plays a significant role in drug discovery. Faced with many stresses and challenges, coupled with being sedentary, plants have developed J o u r n a l P r e -p r o o f many molecules to ward off attacks from animals and environmental insults (Weng et al., 2012) . These phytochemicals show remarkable ability of colours, fragrances and undeniably toxicity. The use of plants by early humans against diseases must have been a trial and error exercise based on necessities. Several plants have been historically used for medicinal purposes including different pathological conditions (Ernst et al., 2015; Gozubuyuk et al., 2014; Hotwani et al., 2014) . Natural products are a pool of drugs especially for anticancer and antimicrobial agents. Despite significant potential, traditional medicine systems, which comprises mostly of natural products, is overshadowed by modern medicine. However, an increased interest towards natural products has been seen from previous few decades in both developing and developed countries due to promising health promontory and medicinal effects. Indeed, several plant extracts are now serving as prescribed drugs in some big nations like Germany, UK, China and France (Ji et al., 2017) . Nearly a quarter of entire EMA and FDA approved drugs are based on phytochemicals, with renowned ones such as morphine and paclitaxel. There are certain drawbacks that make natural products based medicine some times less effective like scarcity of standard procedures, isolation of pure compounds, lesser known biological mechanisms and substandard clinical trials. The therapeutic activity of plant extracts is usually because of the synergistic and simultaneous action of several chemicals. Given the complex nature of many diseases including cancer and degenerative diseases, it is not surprising that the reliance on single compound-based drug discovery has failed to provide effective cures. Plant-based drug discovery therefore must start with a combinatorial approach when evaluating candidate compounds. The advent of novel technologies including quantum computing, profiling techniques, computational biology techniques, big data, microfluidics and artificial intelligence will enable scientists to use a J o u r n a l P r e -p r o o f combinatorial approach to harness the therapeutic properties of plant-based natural products and simultaneously study their molecular effects in physiological conditions (Ozdemir et al., 2018) . It is however possible that not all components of plant extracts have measurable effects. Many antiviral active compounds are too toxic for therapeutic applications. However, natural products remain the best resource for chemically diverse new lead entities that could serve for future development as potent and safe antiviral agents. Recent analysis of the number and sources of antiviral agents reported mainly in the annual reports of medicinal chemistry from 1984 to 1995 indicated that seven out of ten synthetic agents approved by FDA between 1983-1994 are modeled on natural product parent. These drugs are: famciclovir, ganciclovir, sorivudine, zidovudine, didanosine, zalcitabine and stavudine ( Figure 10 ). J o u r n a l P r e -p r o o f The recent COVID-19 outbreak was has effected human race through a number of factors including health and economy. The serious availability of potential drugs and vaccines lacks in almost every corner of the world. Scientists and researchers are working day and night and are leaving no stone unturned in the race for finding efficient and long lasting solutions for COVID-19. Interestingly, more emphasis was laid over exploring natural products against COVID-19 with performing docking and in-vitro investigations. But following the previous track record natural products do not laid us down this time too, they come up with potential agents that can inhibit COVID-19 or prevent its lethal effects. In one such study, a library of about 686 plant based natural products were studied virtually against main protease (Mpro) of SARS-CoV-2 and results showed that 28 had efficient binding energy to Mpro. This study also investigated druglikeness and toxicity of these natural products. Seven out of 28 drugs were found non-toxic rest showed significant toxicity. Those seven include Mpro-Dehydrtectol, Epsilon-viniferin, Peimisine, Gmelanone, and Isocolumbin were non-toxic. These seven compounds showed significant binding efficacy to Mpro and result in stable complex formation and hence could be used as Mpro inhibitors (Sharma et al., 2020) . Not only effective but cost effective and affordable treatments are wanted for COVID-19 due its pandemic form effects all sectors of the societies. A study reported by Gilmore et al. showed in vitro activity of Artemisia annua extracts along with some isolates of the plant like artemether, artesunate and artemisinin ( Figure 11 ). Some of these isolates of the plant have already been approved for anti-malarial activity. The results of their study revealed that subsequent doseresponse based on immunostaining of SARS-CoV-2 spike glycoprotein, in treatment and pretreatment groups with extracts and these isolates showed preventive effects against SARS-J o u r n a l P r e -p r o o f CoV-2 infection in VeroE6 cells. In treatment assays, artesunate (50% effective concentration (EC50): 7 μg/mL) was more potent than the tested plant extracts (128-260 μg/mL) or artemisinin (151 μg/mL) and artemether (>179 μg/mL), while generally EC50 in pretreatment assays were slightly higher (Gilmore et al., 2020) . Therefore, Artemisia annua could be a breakthrough against COVID-19 due to easy availibility, cost effective and natural presence. Nonetheless, such research efforts become the foundation stone for any subsequent drug discovery and provide a guide for further in depth in vivo studies. Middle East respiratory syndrome coronavirus (MERS-CoV): evidence and speculations. Archives of virology Correlation of chest CT and RT-PCR testing for coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases The proximal origin of SARS-CoV-2. Nature medicine Transactions of the Royal Society of London. Series B: Biological Sciences Detection and monitoring of the asymptotic COVID-19 patients using IoT devices and sensors SARS-CoV-2: Virology, epidemiology, immunology and vaccine development Screening of potential drug from Azadirachta Indica (Neem) extracts for SARS-CoV-2: An insight from molecular docking and MD-simulation studies Glycyrrhizin: An alternative drug for the treatment of COVID-19 infection and the associated respiratory syndrome? Programmed ribosomal frameshifting in decoding the SARS-CoV genome Architecture of the SARS coronavirus prefusion spike. Nature structural & molecular biology Biological activities and medicinal properties of neem (Azadirachta indica). Current science Angiotensin-converting enzyme 2-a new cardiac regulator Coronavirus genome structure and replication. Coronavirus replication and reverse genetics Bats: important reservoir hosts of emerging viruses. Clinical microbiology reviews Oxidative stress in alzheimer's disease: A review on emergent natural polyphenolic therapeutics. Complementary therapies in medicine Coronavirus IBV: removal of spike glycopolypeptide S1 by urea abolishes infectivity and haemagglutination but not attachment to cells Severe acute respiratory syndrome vaccine development: experiences of vaccination against avian infectious bronchitis coronavirus. Avian pathology The SARS coronavirus nucleocapsid protein-forms and functions Exploring the active compounds of traditional mongolian medicine agsirga in intervention of novel Coronavirus (2019-nCoV) based on HPLC-Q-Exactive-MS/MS and molecular docking method Evaluation of antiviral activities of Houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection. Asian Pacific journal of tropical medicine Synthesis of cyclopentenyl carbocyclic nucleosides as potential antiviral agents against orthopoxviruses and SARS Targeting Tmprss2, S-protein: Ace2, and 3CLpro for Synergetic Inhibitory Engagement A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19 -2 infection: The role of cytokines in COVID-19 disease. Cytokine & growth factor reviews Human coronaviruses HCoV-NL63 and HCoV-HKU1 in hospitalized children with acute respiratory infections in Beijing, China. Advances in virology Preparation and anti-HIV activities of aurintricarboxylic acid fractions and analogs: direct correlation of antiviral potency with molecular weight Severe lower respiratory tract infection in infants and toddlers from a non-affluent population: viral etiology and co-detection as risk factors. BMC infectious diseases Essential oils as antiviral agents, potential of essential oils to treat sars-cov-2 infection: An in-silico investigation. International journal of molecular sciences The positive sense single stranded RNA viruses Host factors in coronavirus replication. Roles of host gene and non-coding RNA expression in virus infection Aminopeptidase N is a major receptor for the enteropathogenic coronavirus TGEV Further characterization of aminopeptidase-N as a receptor for coronaviruses Genomic and protein structure modelling analysis depicts the origin and infectivity of 2019-nCoV The bittersweet promise of glycobiology Identification of a receptor-binding domain in the S protein of the novel human coronavirus Middle East respiratory syndrome coronavirus as an essential target for vaccine development Cloning of the mouse hepatitis virus (MHV) receptor: expression in human and hamster cell lines confers susceptibility to MHV Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection Natural products as antiviral agents. InStudies in Natural Products Chemistry Global medicinal uses of Euphorbia L. (Euphorbiaceae) Coronaviruses, a new group of animal RNA viruses Alkaloids: Therapeutic Potential against Human Coronaviruses Coronavirus infection, ER stress, apoptosis and innate immunity. Frontiers in microbiology Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Update: severe respiratory illness associated with Middle East respiratory syndrome coronavirus (MERS-CoV)-worldwide, 2012-2013. MMWR. Morbidity and mortality weekly report Drawing Comparisons between SARS-CoV-2 and the Animal Coronaviruses. Microorganisms Artemisia annua Plant Extracts are Active Against SARS-CoV-2 In Vitro Major receptor-binding and neutralization determinants are located within the same domain of the transmissible gastroenteritis virus (coronavirus) spike protein Fractionation and structural elucidation of the active components of aurintricarboxylic acid, a potent inhibitor of protein nucleic acid interactions Severe acute respiratory syndrome coronavirus phylogeny: toward consensus An ancient plant Lawsonia inermis (henna): Determination of in vitro antifungal activity against dermatophytes species The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues Covid-19: natural or anthropic origin? Potent and selective inhibition of SARS coronavirus replication by aurintricarboxylic acid. Biochemical and biophysical research communications Receptor-binding domain of SARS-CoV spike protein induces highly potent neutralizing antibodies: implication for developing subunit vaccine. Biochemical and biophysical research communications Ribosomal production and in vitro selection of natural product-like peptidomimetics: the FIT and RaPID systems SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry Highly conserved regions within the spike proteins of human coronaviruses 229E and NL63 determine recognition of their respective cellular receptors Coronaviruses. In Fields' virology Coronaviruses (Coronaviridae). Encyclopedia of virology SARS coronavirus: a new challenge for prevention and therapy. The Journal of clinical investigation First case of 2019 novel coronavirus in the United States Use of medicinal plants The cytokine storm and COVID-19 Natural products and their derivatives against coronavirus: A review of the non-clinical and preclinical data Significance of physiotherapy in "SARS-CoV-2/COVID-19: An Epidemic Antioxidant effect of aqueous extract of four plants with therapeutic potential on gynecological diseases; semen persicae, Leonurus cardiaca, Hedyotis diffusa, and Curcuma zedoaria Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease Interaction of vitamin C and flavonoids in elderberry (Sambucus nigra L.) during juice processing. Plant foods for human nutrition Direct association of adenosine deaminase with a T cell activation antigen, CD26. Science Plant lectins are potent inhibitors of coronaviruses by interfering with two targets in the viral replication cycle Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures. Voprosy virusologii Polyphenols in the treatment of autoimmune diseases Current approaches for target-specific drug discovery using natural compounds against SARS-CoV-2 infection Medicinal Research Progress of Natural Coumarin and its Derivatives Structure of SARS coronavirus spike receptor-binding domain complexed with receptor Receptor recognition mechanisms of coronaviruses: a decade of structural studies Structure, function, and evolution of coronavirus spike proteins. Annual review of virology Identification of natural compounds with antiviral activities against SARS-associated coronavirus Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. The EMBO journal Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds Identification of residues in the receptor-binding domain (RBD) of the spike protein of human coronavirus NL63 that are critical for the RBD-ACE2 receptor interaction Computational network biology: data, models, and applications Receptor usage and cell entry of porcine epidemic diarrhea coronavirus A unified mechanism for aminopeptidase N-based tumor cell motility and tumor-homing therapy Coronaviruses as Vaccine Vectors for Veterinary Pathogens InViral Vectors in Veterinary Vaccine Development COVID-19: Transmission, prevention, and potential therapeutic opportunities Drug treatment options for the 2019-new coronavirus (2019-nCoV). Bioscience trends Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection. Biochemical and biophysical research communications The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA polymerase Hygromycin B therapy of a murine coronaviral hepatitis. Antimicrobial agents and chemotherapy Natural product-derived phytochemicals as potential agents against coronaviruses: A review. Virus research M13 bacteriophage displaying disulfide-constrained microproteins Review of evidence available on hesperidin-rich products as potential tools against COVID-19 and hydrodynamic cavitationbased extraction as a method of increasing their production Coronaviruses in avian species-review with focus on epidemiology and diagnosis in wild birds Middle East respiratory syndrome coronavirus infection is inhibited by griffithsin The moonlighting enzyme CD13: old and new functions to target. Trends in molecular medicine A novel and Emerging Coronavirus Infection: Repurposing and Scale of Advances of Therapeutics, Imunotherapeutics and Vaccine Development Body fluids may contribute to human-to-human transmission of severe acute respiratory syndrome coronavirus 2: evidence and practical experience. Chinese medicine Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by The receptor binding domain of the new MERS coronavirus maps to a 231-residue region in the spike protein that efficiently elicits neutralizing antibodies Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona-and picornaviruses Coronavirus replication and pathogenesis: implications for the recent outbreak of severe acute respiratory syndrome (SARS), and the challenge for vaccine development Broad-spectrum in vitro activity and in vivo efficacy of the antiviral protein griffithsin against emerging viruses of the family Coronaviridae High throughput virtual screening to discover inhibitors of the main protease of the coronavirus SARS-CoV-2 Identification of novel peptide antagonists for GPIIb/IIIa from a conformationally constrained phage peptide library Birth of industry 5.0: Making sense of big data with artificial intelligence, "the internet of things" and next-generation technology policy Bacterial Cell-Surface Display of Semisynthetic Cyclic Peptides In silico studies reveal potential antiviral activity of phytochemicals from medicinal plants for the treatment of COVID-19 infection Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors Glycosylation of the viral attachment protein of avian coronavirus is essential for host cell and receptor binding Crystal structure of bovine coronavirus spike protein lectin domain Phase I safety, tolerability, and pharmacokinetic study of recombinant human mannanbinding lectin Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations. The Lancet Respiratory Medicine Biomarkers associated with COVID-19 disease progression. Critical reviews in clinical laboratory sciences Mapping of the receptor-binding domain and amino acids critical for attachment in the spike protein of avian coronavirus infectious bronchitis virus The COVID-19 cytokine storm what we know so far. Frontiers in immunology Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC TRADITIONAL TO RECENT APPROACHES IN HERBAL MEDICINE THERAPY OF COVID-19 Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2). Pharmacological research Nature as a treasure trove of potential anti-SARS-CoV drug leads: a structural/mechanistic rationale Neuraminidase treatment of avian infectious bronchitis coronavirus reveals a hemagglutinating activity that is dependent on sialic acid-containing receptors on erythrocytes The S protein of bovine coronavirus is a hemagglutinin recognizing 9-O-acetylated sialic acid as a receptor determinant Sialic acids as receptor determinants for coronaviruses. Glycoconjugate journal The Antiviral, Anti-Inflammatory Effects of Natural Medicinal Herbs and Mushrooms and SARS-CoV-2 Infection Identification of natural inhibitors against Mpro of SARS-CoV-2 by molecular docking, molecular dynamics simulation, and MM/PBSA methods High-throughput screening and identification of potent broad-spectrum inhibitors of coronaviruses Plants-derived biomolecules as potent antiviral J o u r n a l P r e -p r o o f phytomedicines: New insights on ethnobotanical evidences against coronaviruses A review of coronavirus disease-2019 (COVID-19). The indian journal of pediatrics A unifying structural and functional model of the coronavirus replication organelle: Tracking down RNA synthesis World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19). International journal of surgery Continuous and discontinuous RNA synthesis in coronaviruses. Annual review of virology Antiviral activity of ginsenosides against coxsackievirus B3, enterovirus 71, and human rhinovirus 3 Coronavirus: Comparing COVID-19, SARS and MERS in the eyes of AI Nutraceuticals and herbal extracts: A ray of hope for COVID-19 and related infections Polyphenol-based nutraceuticals for the prevention and treatment of cardiovascular disease: Review of human evidence Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants Plant Products as Potential Antiviral Agents The COVID-19 epidemic. Tropical medicine & international health Natural and Nature-Derived Products Targeting Human Coronaviruses Lycorine: a eukaryotic termination inhibitor? Cryo-electron microscopy structure of a coronavirus spike glycoprotein trimer Mask use during COVID-19: A risk adjusted strategy. Environmental Pollution Viruses in bats and potential spillover to animals and humans. Current opinion in virology Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell research An updated and comprehensive review of the antiviral potential of essential oils and their chemical constituents with special focus on their J o u r n a l P r e -p r o o f mechanism of action against various influenza and coronaviruses. Microbial Pathogenesis COVID-19 diagnostics in context. Science translational medicine Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus The rise of chemodiversity in plants Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway. Cancer research Situation Report, Data as received by WHO from national authorities by 6 th Receptor for mouse hepatitis virus is a member of the carcinoembryonic antigen family of glycoproteins A 193-amino acid fragment of the SARS coronavirus S protein efficiently binds angiotensin-converting enzyme 2 Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods The use of one-bead one-compound combinatorial library technology to discover J o u r n a l P r e -p r o o f high-affinity αvβ3 integrin and cancer targeting arginine-glycine-aspartic acid ligands with a built-in handle Severe COVID-19: a review of recent progress with a look toward the future. Frontiers in Public Health Molecular model of SARS coronavirus polymerase: implications for biochemical functions and drug design. Nucleic acids research Clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by SARS-CoV-2 Crystal structure of the post-fusion core of the Human coronavirus 229E spike protein at 1.86 Å resolution Targeting coronaviral replication and cellular JAK2 mediated dominant NF-κB activation for comprehensive and ultimate inhibition of coronaviral activity. Scientific reports Identification of phenanthroindolizines and phenanthroquinolizidines as novel potent anti-coronaviral agents for porcine enteropathogenic coronavirus transmissible gastroenteritis virus and human severe acute respiratory syndrome coronavirus Understanding human-virus protein-protein Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-A possible reference for coronavirus disease-19 treatment option Structural analysis of inhibition mechanisms of aurintricarboxylic acid on SARS-CoV polymerase and other proteins. Computational biology and chemistry SARS and other coronaviruses as causes of pneumonia Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorganic & medicinal chemistry letters In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus Clinical trials for the treatment of Coronavirus disease 2019 (COVID-19): A rapid response to urgent need Coronavirus replication does not require the autophagy gene ATG5 Monoclonal antibodies for the S2 subunit of spike of SARS-CoV-1 cross-react with the newly-emerged SARS-CoV-2 Virus-encoded proteinases and proteolytic processing in the Nidovirales SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease 2019: a review Coronaviruses-drug discovery and therapeutic options. Nature reviews Drug discovery The authors declare that there is no conflict of interest to indicate.