An Overview of COVID-19 and the Potential Plant Harboured Secondary Metabolites against SARS- Cov-2: A Review

The SARS-CoV-2 virus causes COVID-19, a pandemic disease, and it is called the novel coronavirus. It belongs to the Coronaviridae family and has been plagued the world since the end of 2019. Viral infection to the lungs causes fluid filling and breathing difficulties, which leads to pneumonia. Pneumonia progresses to ARDS (Acute Respiratory Distress Syndrome), in which fluid fills the air sac and seeps from the pulmonary veins. In the current scenario, several vaccines have been used to control the pandemic worldwide. Even though vaccines are available and their effectiveness is short, it may be helpful to curb the pandemic, but long-term protection is inevitable when we look for other options. Plants have diversified components such as primary and secondary metabolites. These molecules show several activities such as anti-microbial, anti-cancer, anti-helminthic. In addition, these molecules have good binding ability to the SARS-CoV-2 virus proteins such as RdRp (RNA-dependent RNA polymerase), Mpro (Main Protease), etc. Therefore, these herbal molecules could probably be used to control the COviD-19. However, pre-requisite tests, such as cytotoxicity, in vivo, and human experimental studies, are required before plant molecules can be used as potent drugs. Plant metabolites such as alkaloids, isoquinoline ß-carboline, and quinoline alkaloids such as skimmianine, quinine, cinchonine, and dictamine are present in plants and used in a traditional medicinal system.

RdRp inhibition by nucleotide inhibitors is revealed by studying the RdRp complex (substrate RNA and Remdesivir), and it provides a molecular blueprint for developing RdRp-targeting medicines 8 .
P l a n t s e c o n d a r y m e t a b o l i t e s (PSM) in plants help combat biotic stresses (microorganisms, insects, parasites) and abiotic stresses (temperature, pH, water activity, heavy metals). In addition, these PSMs are also useful for humans, so plant and plant parts are used as nutraceuticals, drugs, and foodstuffs [9][10][11] . Plant secondary metabolites (PSMs) exhibiting antiviral activities by disturbing the viral particle constituents such as protein, lipid envelope, and genetic materials such as DNA or RNA of a virus particle. The lipid envelope of viruses is disturbed by lipophilic terpenoids of essential oils, membrane-bound viral proteins, and the viral particle's inside the host tackled by phenols and polyphenols of plants. Moreover, free virus particles are more susceptible than the virus present in the host cell to both phenolics and essential oils of plants 12 .
Furthermore, DNA intercalators such as berberine, ß-carboline, emetine, isoquinoline alkaloids, sanguinarine, and quinoline alkaloids such as cinchonine and quinine skimmianine, as well as dictamen also effectively inhibit the viral genome replication 12 . By blocking viral proteins and blocking virus entry into the host cell, perhaps PSMs play a key role in preventing COVID-19 from spreading. In vitro research using pomegranate peel extracts revealed an interaction between the spike glycoprotein of SARS-CoV-2 and the ACE-2 (Angiotensin-Converting Enzyme 2) receptor that prevents and inhibits the virus's 3CL protease activity 10 .
In this present review, an overview of coronavirus, also known as COVID-19, as well as its symptoms, disease progression, infection mechanism, virus replication, control measures, treatments, and immunization were covered. The virtual drug screeing (in silico) methods including molecular docking and molecular dynamics simulation studies are also covered. Moreover, the ability of plant secondary metabolites to be active against COVID-19 in vitro and in vivo studies has also been documented.

COviD-19 Symptoms
COVID-19 exhibits various symptoms from mild illnesses to chronic and multi-organ failure, leading to older age patients. The most common COVID-19 symptoms include fever, cough, lung auscultation/oxygen saturation; however, this data may be used to rule out patients with COVID- 19  Complete and near-complete genetic analyses of SARS-CoV-2 showed several deletions as well as mutations on coding and non-coding regions, indicating the virus's genomic variety and fast evolution 20 . Furthermore, a 4 per cent difference in genomic nucleotide variation was found between SARS-CoV-2 and another coronavirus related to SARS, such as bat's SARSlinked coronavirus (SARSr-CoV, RaTG13) 21 .
The SARS-CoV-2 spike binds to human ACE-2 (hACE2), a receptor by its RBD (receptorbinding domain), and proteolytic reactions activate proteases. Furthermore, the pseudovirus entry test revealed that RBD of SARS-CoV has lesser binding compatibility than SARS-CoV-2 RBD with hACE2. In addition, the spike of SARS-CoV-2 is shorter than the SARS-CoV, which is helpful in binding hACE2 and also useful to minimize exposure to cell defence. Furthermore, the high hACE2-binding affinity to RBD, spike's furin preactivation, and hidden RBD present in SARS-CoV-2 spike are potentially helpful in evading the immune system and successful cell entry 22 .
Enzymes play a crucial part in the development of the disease, and they are also possible therapeutic hotspots. Four key enzymes of SARS-COV-2, such as RdRp, 3CLp, papain-like protease, helicase, and ACE-2; and transmembrane serine protease (Host factors), play an essential role in disease establishment. Interestingly, α-glucosidase in the endoplasmic reticulum is a promising target for exploring anti-SARS-CoV-2 medicines 23 .

Immunology of COVID-19
Humoral and cell-mediated immunity of both types of immune responses is particularly prominent when COVID-19 infection occurs. However, cell-mediated immunity is prime and effective against viral infections 29 . In COVID-19 patients, abnormal lymphocyte distribution, an increase in mature natural killer cells (NK), and a decrease in T cells have been identified. NK cells overexpressed T-cell immunoglobulin, mucin-3 domain (TIM-3), and CD69, as well as CD8+ T cells, were also reported. NK cell exhaustion was identified by increased PD-1 (Programmed Cell Death Protein 1) frequencies in positive cells, NKG2D DNAM-1 frequencies were decreased [Natural Killer Group 2 D (NKG2D)-DNAX accessory molecule-1 (DNAM-1)], and Siglec-7 (sialic acidbinding Ig-like lectin 7) expressing NK cells, and interferon (IFN) secretion ability reduced. Further, interferon (IFN)γ secretion ability also reduced observed, and serum IL-6 levels were higher in deceased patients than in survivors 30 . Plasma levels of interleukins 2, 7, and 10, GSCF, MIP1A, IP10, MCP1, and TNF were higher in ICU admissions patients than in non-ICU patients, indicating that the severity of the disease had increased 16 .
A gradual decrease in viral load and increased antibodies have been reported in patients after one week of infection. According to the study, the viral load was highest during the first week and dropped by the second week. Furthermore, antibodies such as IgG and IgM are often detected 10 days after viral infection, and these play an essential role in neutralizing the SARS-COV-2 virus 31,32 .
Further, antibodies produced from coronavirus variant 501Y.V2 are also effective against the previously reported coronavirus variants. Therefore, the vaccine from the 501Y.V2 variant can be used against a variety of coronavirus strains 33 .

Mode of transmission of SARS-Cov-2
The transmission of SARS-CoV-2 occurs by contact and droplet transmission, airborne transmission, fomite transmission, and other modes of transmission, such as faecal-oral contamination, blood-borne transmission, transmission from mother to child, and transmission from animals to humans 34,35 .

COVID-19 protective measures
According to the WHO guidelines, wash or clean the hands frequently or often, while coughing or sneezing use the bent elbow, touching of eyes, nose, and mouth with hands, avoid social gatherings and crowded places, make a suitable distance from the sick, disinfect, and clean touched objects and surfaces 35 . Furthermore, WHO recommendations suggest identifying suspicions early and testing them as soon as feasible and isolating sick people in appropriate facilities. As early as possible, identify and quarantine all intimate contact with infected people, and will be tested and take appropriate actions for those who show symptoms. Fabric masks are used in public areas and to provide physical separation where there is a risk of communicable disease transmission. Health workers should be taken care of not to contact and droplets formed by COVID-19 patients, and aerosol production avoided. Health workers advise continuous usage of a medical mask throughout the shift for all normal activities. Hygiene at all times, physical separation, avoidance of crowded areas, close-contact situations, and cramped and enclosed rooms with poor ventilation are all recommended 34 . vaccines for COviD- 19 There are several vaccine candidates used today, and a mass vaccination program started in several countries. Vaccines such as Johnson & Johnson's, Moderna, AstraZeneca, Pfizer-BioNTech, Janssen, Covaxin, Covishield, etc., are widely used in mass vaccination programs around the world. The types of vaccines used for COVID-19 are mRNA vaccines, protein subunit vaccines, and vector vaccines. It usually takes several weeks after vaccination for the organism to produce T and B lymphocytes. Therefore, it is possible for humans to get an infection and become sick from a virus just before or after vaccination due to didn't have time for protection. The immunization induces Macrophages, B-lymphocytes, and T-lymphocytes are responsible for immunity development 36

PSMs against COVID-19
In the evoke of the second wave of COVID-19, medicines are used for a short time so far, no particular medicine is not available for this disease, and the drug discovery process is ongoing. The plants are well-known producers of many low molecular weights based on the inferred functions classified into primary and secondary metabolites and hormones. Plant growth relies heavily on primary metabolites; hormones helpful in organism activities and metabolism; secondary metabolites play an essential role in plant-environment interactions, plant defence, etc. Interestingly, the boundary of activity of these metabolites is not fully known, so a comprehensive study on the effect of the activity of these molecules needs to be conducted 39 . The diverse phytochemicals such as terpenoids, organosulfur compounds, flavonoids, sulphides, limonoids, lignans, alkaloids, polyenes, polyphenolics, coumarins, saponins, thiophenes, chlorophyllins, furyl compounds, peptides, and proteins exhibit antiviral activities against a wide array of viruses 40 . Table 1 lists prospective phytochemicals and their inhibitory effect on SARS-CoV-2, whereas Table  2 lists medicinal plants and their prospective phytochemicals that are effective against SARS-CoV-2. The protein sequences of SARS-CoV-2 3CLpro and SARS-CoV 3CLpro were 99.02 per cent identical. According to molecular docking and molecular dynamic simulation studies, about 9 active phytochemicals suggested as SARS-CoV-2 antiviral molecules based on their docking score and binding affinity 41 . Artificial or virtual natural drug molecules screening methods for SARS-CoV-2 Bioactive compounds are constantly being investigated in creating novel bioactive molecules with industrial uses, gaining attention from the scientific community due to their pharmacophorelike structures, pharmacokinetic qualities, and chemical space 42 . Computational approaches have revolutionised the identification of novel specific bioactive compounds by evaluating vast structural libraries in silico against a bioreceptor or biological system, lowering the cost, facilities, and time to identify new compounds 42,43 . Machine learning-based models trained on specific proteins have provided affordable and quick-to-implement approaches for the development of successful viral treatments in the recent decade. These models can forecast inhibitor candidates in a structuralbased way given a target biomolecule 44,45 . Artificial intelligence (AI) uses reasoning, representation of knowledge and solution-oriented search; however, machine learning (ML) play an key role in this. ML is a type of machine learning that employs algorithms to detect patterns in a set of data that has been further categorised. Deep learning (DL) is a branch of machine learning that uses artificial neural networks (ANNs) which are mimicking of human neurons kind 45,46 . With the low cost various in silico methods helpful to analyze the virtual chemical gaps considering with ligand interaction and structure in drug discovery process. To choose a lead molecule, drug design methods such as coulomb matrices and molecular fingerprint recognition analyse the physical, chemical, and toxicological characteristics 47,48 . Various AI tools such as DeepChem, Deep Neural Net QSAR, DeltaVina, AlphaFold, ORGANIC etc., are using in the drug discovery method, protein folding, ligand interaction study 45 .
A virtual drug screening comprises mainly library preparation and suitable computational techniques. Library preparation consists of structure of compounds obtaining and convert them into readable formats like SMILES, SDF and MOL2 (simplified molecular-input line entry system, structure data file and MDL Molfile). The computational techniques includes both  Boerhavisterol, kaempferol, Boeravinone J, Quercetin, Liriodendrin, Trans − caftaric acid, 2-3-4 beta-Ecdysone SBVS-structure-based virtual screening or LBVSligand based virtual screening. After the library prepartion, computational techniques employed and finally in silico results validating by in vitro and in vivo assays 42 . The majority of machine learning drug discovery studies of SARS-CoV-2 focused on viral protiens such as spike (S) protein, MPro, 3CLPro etc., protein ligand interaction, binding effeciency, and binding free energy are also considered in the process 44,49,50 . The studies on SARS-CoV-2 drug discovery focused on the sequence of target proteins such as 3CLPro, S protein, ACE-2, Main Protease, RdRP and host TMPRSS2 protease ACE2 receptor are considered. Later by adapting the deep docking, QSAR etc., are using to identify the protein inhibitors from available databases like FDA approved drugs, ZINC database etc. In majority of studies 3CLPro of SARS-CoV-2 is target protein, Deep learning model and molecular dynamic simulation methods approched to finilise the highest hit compound to target protein like 3CLPro of SARS-CoV-2 42,44,49-53 . Some of the extracts of litchi seeds, Houttuynia cordata, Chinese Rhubarb extracts, Isatis indigotica plants (beta-sistosterol) root extract can inhibit the SARS enzymatic activity 54 . In addition, immune-modulating supplements such as Echinacea purpurea consumption may prevent the infection 55,56 . Around 219 plants from 83 families showed antiviral activity and screened the major plant secondary metabolites (PSMs) from 149 plants of 71 families for the COVID-19 pandemic 57 . The computer simulation (in silico) studies come out with phytochemicals such as glycyrrhizic acid, 7-deacetyl-7-benzoylgedunin, limonin, maslinic acid, obacunone, corosolic acid, and ursolic acid are effective against some proteins of SARS-CoV-2. These studies majorly focused on viral proteins such as PLpro, SpG-RBD, 3CLpro, RdRp, and ACE-2 58 .
Plants ubiquitously have a diversified flavonoid known as natural health products and chemically showed a 15-carbon skeleton of C6-C3-C6 with different subclasses based on structural configuration. The major subclasses of flavonoids are flavanols or catechins, flavones, flavonols, flavanones, anthocyanins, and isoflavones 59 .
Triterpenoids are large group of phytochemicals, which are metabolites of isopentenyl pyrophosphate oligomers 62 . Triterpenoids are naturally found in Oleanolic, betulinic, and ursolic acid forms, and they exhibit a broad spectrum of antiviral, antitumor, and antiinflammatory activities 63 .
In a study, among selected plant secondary metabolites, superior molecule triterpenoids exhibited lower binding energy (> 50%) and firmly interacted with the viral receptor-binding domain of spike protein. Further, flavonoids and glycosides exhibited > 32% of interaction with the human transmembrane serine protease active site. The lower binding energy was exhibited by flavonol glycosides and anthocyanidins with > 16% of the viral main protease active site. Interestingly, the glycoside of flavonol interacts very firmly with viral RNA-dependent RNA polymerase (>13%). Some Triterpenoid plant secondary metabolites, including Coagulins, Withanolides, Pseudojervine, and others, can actively inhibit the AARs of spike protein, which interacts with hACE2, blocking host cell detection by SARS -CoV-2 64 .
Saponins are the glycosides of triterpenes and steroids that occur naturally in non-volatile and surface-active glycosides and exhibit various pharmacological activities. Saponins have antiviral action and perhaps be used as vaccine adjuvants in mammals because of their capacity to stimulate and activate the immune system 65 .
Alkaloids are significant plant secondary metabolites with a nitrogen atom or elements like amino or amido groups in their structure, which results in alkalinity. Alkaloids are cyclic structure ones based on a structure divided into isoquinolines, pyrrolizidines, quinolines, pyridines, isoquinolines, pyrrolidinestropanes, indoles, and terpenoids and steroids 66 .
Alkaloids from medicinal plants of Africa may interrupt cell entry of SARS virus by attaching with spike glycoprotein, human cell receptor ACE-2 blocking and inhibiting the host cell serine protease TMPRSS2 67 . The in vitro study of alkaloids such as Berberine and Obatoclax effectively inhibited replication of SARS-Cov-2 in human nasal epithelial cells. However, efficacy tests are required for further usage as potential antivirals. It is interesting to note that Obatoclax showed its effectiveness at early steps in the life cycle of a virus, such as entry processes. On the other hand, berberine was more active in the later phases of the viral life cycle, suggesting that it may limit the infectivity of newly generated virions 68 .
A polyphenolic colourless crystalline oxygenated heterocyclic compound is called Coumarins. Coumarins are naturally found in free forms, and their 800 derivatives are reported from 600 genera of several plants' families 69 . Coumarins used as therapeutic agents and a molecular docking study showed that coumarin analogues such as toddacoumaquinone and synthesized coumarin analogue (1 m) had 7.8 kcal/ mol to be the binding energy and −7.1 kcal/mol, respectively 70 .
M e t h y l t r a n s f e r a s e ( M Ta s e ) , Endoribonuclease (endoU), and ADP ribose Phosphatase are required for the survivability of SARS-CoV-2 Main Protease enzymes (Mpro). Coumarins showed inhibits these proteins and exhibited antiviral activity, i.e., showed in in silico studies, -9.00 to -7.97, -8.42 to -6.80, -8.63 to -7.48 and -7.30 to -6.01 kcal/mol, of docking score recorded against Methyltransferase, Endoribonuclease, and Main Protease components of virus 71 .

Food ingredients and other active products
Food is a vital component of life. Meanwhile, it supports the organism free from infection by improving or boosting their immunity. In addition, lipids, which are found in foods, are essential in the virus's suppression. Unsaturated fatty acids like arachidonic acid (AA), icosapentinoic acid (EPA), and docosahexaenoic acid (DHA) help reduce the inflammation, in addition to this promote wound healing, enhance macrophage and another immune cell phagocytosis, and reduce microbial load, may these activities affect the virus and acts as antiviral molecules. Perhaps after validation, oral or intravenous administration of these will increase the resistance and recovery from SARS-CoV-2 72 .
Nutraceuticals include Ferulic acid, Lipoic acid, Spirulina, N-Acetylcysteine, Selenium, Glucosamine, Yeast Beta-Glucan, Zinc, Elderberry recommended to control coronavirus and influenza. For instance, these enhance the response of type 1 interferon to RNA viruses 73 . In addition, the docking studies revealed that Phycocyanobilin, Riboflavin, Cyanidin, Daidzein, Genistein are bioactive components of food that potentially inhibit Mpro and RdRp in the SARS-CoV-2 virus 74 .

CONCluSiON
The plant extracts showed inhibitory action against pathogens. Bio-active components such as primary and secondary metabolites play an essential role in viral inhibition. The structure of these molecules may interrupt the attachment to the host, entry of virus particle, arrest the virus replication mechanism, interact with their genome and inhibit the disease establishment. Herbal medicine is an ancient medicine technique that exists from human existence, and nature provides many valuable molecules to human beings through plants. Plants and their products are used as food, and some are used as medicinal plants; these possess secondary metabolites protecting human beings from several diseases by improving immunity. Several plant-based components showed excellent binding capacity toward SARS-COV-2 virus proteins such as Mpro and other proteins compared with standard synthetic drugs used today. Therefore, still effective medication comes to COVID-19, the herbal-based components are a golden token to control the disease. However, the proper validation with thorough in vitro, in vivo and clinical trials of plant compounds is essential to confer before use as a drug.

ACKNOwleDgMeNtS
I would like to thank Central Council