Role of phytoconstituents in the management of COVID-19.

Introduction

The ongoing global COVID-19 pandemic still remains a major challenge for scientific communities since its outbreak in December 2019 and has become one of the major causes of mortality and morbidity in large populations. As of June 19, 2020, the World Health Organization (WHO) reported that 213 countries and territories have been affected from this deadly infectious disease originated from Wuhan, China with 8,585,194 infected and 456,439 death cases confirmed worldwide Fig. 3 [ 1 ]. COVID-19 has not only affected the global health care system but also hampered the economic growth of the countries along with changes in the normal lifestyle and habits [ 2 , 3 ]. COVID-19, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is recognized as a communicable and deadly respiratory illness, which begins with normal common cold symptoms and become adverse with course of time leading to fever, dry cough and shortness of breath [ 4 , 5 ]. Certain morbidity factors such as hypertension, cardiovascular diseases, diabetes mellitus, pollution and age increase the risk of COVID-19 [ 6 , 7 ].

Coronavirus was first discovered in animals and birds commonly in bats and cats in mid-1960s and found to spread to human by zoonotic transmission [ 8 , 9 ]. The coronaviruses went unrecognised globally until the SARS-CoV pandemic emerged in 2002–03 in Guangdong China, which caused severe acute respiratory syndrome (SARS) infecting more than 8000 people with 800 deaths, followed by Middle east respiratory syndrome (MERS-CoV) which emerged in 2012 in Saudi Arabia infecting nearly 2300 people with 850 deaths [ 10 , 11 ]. At the end of December 2019, a novel coronavirus infected several numbers of people in Wuhan, China. On January 2020, this novel virus was named as 2019‐nCoV officially by WHO and in the same month, several countries became the victim of this deadly infectious virus [ 12 ]. Therefore, we can say that coronavirus mediated infections occur periodically in different areas of the world. The 2019 novel coronavirus shows 88% sequence similarity with bat derived SARS-CoV and 50% similarity with MERS-CoV [ 13 ]. WHO estimated the reproductive number (R 0 ) for SARS-CoV-2 between 2 and 2.5 higher than the SARS-CoV which is 1.7–1.9 and MERS with <1, thus a higher potential of spreading with mortality rate of COVID-19 is 2.3% which is less than that of SARS (~9.5%) and MERS (34.4%). According to various genomic and in vitro analyses, it is clear that SARS-CoV-2 shares same host cell entry receptor as SARS-CoV, i.e., angiotensin converting enzyme-2 (ACE-2) while MERS-CoV uses dipeptidyl peptidase (DPP4). Similar to earlier SARS-CoV and MERS-CoV, the novel SARS-CoV-2 infects part of lungs and thus causes bilateral peripheral pneumonia with multiple organ failures and thus has been declared more contagious than earlier SARS and alveolar MERS [ [14] , [15] , [16] ]. Table 1 includes the comparative data between SARS-CoV, MERS-CoV and SARS-CoV-2 in terms of their origin, host, transmission, symptoms, incubation period, recovery, etc. Table 1 Comparative data of SARS-CoV, MERS-CoV and SARS-CoV-2 [ 14 , 17 , 18 ]. Table 1 SARS-CoV MERS-CoV SARS-CoV-2 Origin Southern China Saudi Arabia Wuhan, China Host Palm civets Camel Not known Transmission Through close contacts between human to human Touching infected camels or consuming their milk or meat Human to human transmission through close contacts Symptoms (major) Fever, dry cough, headache, difficulty in breathing, muscle aches, loss of appetite, diarrhoea Fever, chills, diarrhoea, nausea, vomiting, sneezing, congestion, sore throat Fever, fatigue, cough, shortness of breath Incubation Period 2–7 days 5–6 days 2–14 days Recovery 5–6 weeks 6–7 weeks 2–8 weeks Treatment No vaccines available, antiviral medicines No vaccines available, only drugs for symptoms are available No vaccines available, only existing drugs are in use for symptoms Countries effected 29 26 >140 Fatality Rate 9.5% 34.4% 2.3%

Family of coronaviruses

According to International Committee on Taxonomy of Viruses, coronaviruses come under subfamily of Coronavirinae from the family Coronaviridae and order Nidovirales ( Fig. 1 ) [ 19 ]. The Coronavirinae subfamily is further divided into four genera, i.e., alpha-coronavirus, beta-coronavirus, gamma-coronavirus, and delta-coronavirus [ 20 ]. First two infect only mammals and rest infect birds and in some case mammals too. The alpha-coronaviruses include human coronavirus NL63 (HCoV-NL63), porcine transmissible gastroenteritis coronavirus (TGEV), PEDV, and porcine respiratory coronavirus (PRCV), whereas the beta-coronaviruses include SARS-CoV, MERS-CoV, bat coronavirus HKU4, mouse hepatitis coronavirus (MHV), bovine coronavirus (BCoV), and human coronavirus OC43. The gamma-and delta-coronaviruses include avian infectious bronchitis coronavirus (IBV) and porcine delta-coronavirus (PdCV), respectively [ 21 ]. The alpha-coronaviruses and beta-coronaviruses result into pulmonary illness in humans and cholera infantum in animals [ 22 ]. MERS-CoVs are deadly pathogenic viruses causing serious respiratory problem in humans, while other viruses like SARS-CoV and HCoV- NL63, HCoV-229E, HCoV-OC43 and HKU1 do not result into critical conditions compared with the earlier. Domestic animals are the sources for transmission of these viruses from natural host to humans [ 23 ]. Data collected from various databases show that all the human coronaviruses originated from animals such as SARS-CoV, MERS-CoV, HCoV-NL63 and HCoV-229E originated from bats [ 24 ]. These studies concluded that bats are mainly responsible for transmission of these. SARS-CoV-2 also has been found to be originated from bats and further spread to human by zoonotic transmission according to reports published [ 25 ]. Fig. 1 Family of coronaviruses. Fig. 1

The SARS-CoV-2 is a single stranded, enveloped, large positive sense RNA virus with a size of nearly 125 nm and genome size of 27–32 kb [ 17 ]. The virus contains four structural proteins i.e., envelope protein (E), membrane protein (M), spike protein (S) and nucleocapsid protein (N) ( Fig. 2 ). Viral genome is packed within nucleocapsid (N) with a shell of envelope outside [ 26 ]. This envelope is associated with other three structural proteins (M, S, and E) having different functions; the membrane protein is a transmembrane glycoprotein which helps the virus in developing capsid and structure assembly whereas envelope protein is involved in virus packaging and spike protein helps entry into host cells [ 27 ]. The spikes are responsible for the formation of large protrusion and thus gives them the shape of crown and hence the name corona meaning crown in Latin [ 28 ]. Fig. 2 Schematic diagram of SARS-CoV-2 structure. Reproduced from Ref. [ 29 ] with permission from Elsevier. Fig. 2

Currently there is no specific treatment for this deadly infectious disease except quarantine and symptomatic treatment protocol for disease management [ 29 ]. As it is clear from different reports that the sequence homology of SARS-CoV and SARS-CoV-2 is nearly similar but the transmission efficiencies are different which are probably due to changes in the nucleotide sequences in spike protein (S) and receptor binding domain [ 30 ]. Medical practitioners are using existing drugs for controlling the symptoms and a community of researchers globally are involved in developing new drug modalities and vaccines since past 8 months, however no success has been met so far and it may still take months to years in developing the same [ 31 ]. Considering the high virulence of SARS-CoV-2, it is imperative to develop new preventive or therapeutic agents at the earliest to control the current pandemic situation. Bioactive molecules from plants have served as invaluable sources of different therapeutic drugs and are being used in the treatment of various diseases around the world. Medicinal plants are also being explored in management of COVID-19 pandemic in two ways, i.e., either as immunomodulators or viral target inhibitors based on their established roles in managing other viral diseases. The secondary metabolites and other chemical compounds from plants could prove as promising therapeutic agents as antiviral either by inhibiting the viral replication or viral cell entry and/or otherwise treating the underlying infection caused by SARS-CoV-2 and thus could prove a safer and innovative treatment for this viral infectious disease [ [32] , [33] , [34] , [35] ].

This review has thus been planned to list the potential phytomoieties and their plant sources which can be used as inhibitor molecules targeting either the host cell or SARS-CoV-2 therapeutic receptors in providing a safer and long-term solution for the population with lesser side effects.

Coronavirus infection mechanism

The SARS-CoV-2 share some sequence homology with SARS-CoV but show different transmission potential and infection range [ 36 ]. The ongoing COVID-19 disease is seen as more treacherous with still no treatment and could be potentially due to certain functional mutations occurring in the SARS-CoV-2. The major differences observed in SARS-CoV-2 are absent 8a, longer 8b and shorter 3b segments and different Nsp-2 and -3 proteins. Along with these, the open reading frames are also different in some places like in orf8 and orf10 [ 17 ]. The process of infection is totally dependent on the interaction between virus and the host cell and begins when the viral particles get attached to the cell surface receptor of the host cell and it delivers the nucleocapsid inside the target cell membrane. The main function is provided by S-protein in binding and fusion with the host cell membrane. SARS-CoV-2 binds with the same receptor ACE-2 present in respiratory epithelium and alveoli of lungs, as SARS-CoV. Fusion takes place because of gain of conformational changes by the spike protein and the process depends upon two factors i.e., pH acidification and proteolytic activation [ [36] , [37] , [38] , [39] ] ( Fig. 3 ). The S-protein is homotrimeric with each subunit having two domains S1; the receptor binding domain and S2; the membrane fusion domain enabling the virus to enter the host cell. After fusion, the cleavage of fusion protein is the prime event for further process of infection and it is the main characteristic of class I viral fusion proteins [ 40 ]. Fig. 3 Schematic diagram of coronavirus infection. Reproduced from Ref. [ 12 ] with permission from Elsevier. Fig. 3

S protein is cleaved by proteases into two domain S1 and S2, of which S2 domain is responsible for entering fusion protein inside the membrane of host cell and ultimately facilitating the entry of virus into the cell [ 17 , 36 ]. Unlike SARS-CoV-2, some coronaviruses like MHV-2 and SARS-CoV do not need cleavage of spike protein for entering purpose, they can directly enter inside the cell with the presence of exogenous proteases and this process is 100–1000 fold efficient than the endosomal pathway. Proteases like transmembrane protease/serine family (TMPRSS) and human airway trypsin like protease (HAT) both induce the fusion of SARS-CoV-2 [ 41 , 42 ]. Once the fusion occurs and fusion protein enters the host cell, ACE-2 gets cleaved and it is covered by ADAM17 in extra membranal space which convert angiotensin I to angiotensin II, a negative regulator of renin angiotensin pathway and this reduced ACE-2 is responsible for respiratory injury and illness [ 43 ]. Once viral protein gets translated into the cell, various pathways gets activated and are associated with spreading of infection. An ORF3a protein code for Ca +2 ion channel and activates transcription of NF-kB pathway by interacting TRAF3. The ORF8b protein activates the inflammasome pathway through NLRP3. All these pathways result in overproduction of cytokines and thus cause respiratory problems. JNK pathway is also activated by ORF3a, ORF3b and ORF7a which is responsible for lung disorders [ 17 , 44 , 45 ]. The viral infection can be minimized if the virions do not bind to the cell and this can be done by inactivating the virus. SARS-CoV-2 binds more strongly to the receptor ACE-2 than the SARS-CoV and therefore infection transmission rate and virulence is much higher than the SARS-CoV [ 46 ]. TMPRSS2 associated with ACE-2 is responsible for spreading the infection at initial stages and thus could be another therapeutic target for the new drug discovery [ 47 ].

Therapeutic targets

Currently there are no approved specific treatments or drugs to treat COVID-19 except the clinical management such as infection prevention, control measures and life supportive care [ 48 ]. The prevailing conditions of current pandemic such as re-emergence of infection cases, uncontrolled transmission and morbidity associated with the disease are crippling the healthcare systems with grave effects on the global economies and posing a challenging situation for health practitioners and scientists to identify the therapeutic strategies to handle this problem [ 49 ]. Therapeutic repurposing of existing drugs like anti-malarials, antivirals, and NSAIDs etc., has been used as an effective approach in management of COVID-19 with drugs inhibiting either the different viral receptors/enzymes or the host cell receptors. Identification of drug targets (viral or host cell) remains one of the important criteria for the discovery of new molecules as well as to check the therapeutic efficacy of existing drug molecules [ 13 , 50 ]. The below section briefly enlists the potential therapeutic targets along with the current drugs repurposed towards these targets.

Angiotensin converting enzyme-2 (ACE-2)

ACE-2 is the functional receptor of SARS-CoV-2 and is a negative regulator of renin angiotensin system (RAS) [ 51 ]. The S-proteins of SARS-CoV-2 get attached with ACE-2 receptor of the host cell in a much stronger manner compared to the SARS-CoV thus producing higher pathogenicity [ 52 ]. Many reports have suggested that ACE-2 could be one of the possible COVID-19 targets as it can block the binding of the virus with the host cell and thus blocking the viral cell entry. Therapeutic options for blocking the viral entry utilizing neutralizing antibodies such as soluble receptor binding domain that could occupy ACE-2 and soluble ACE-2 are envisaged as possible viral trap and thus inactivators of SARS-CoV-2 [ 53 ]. Despite the initial controversy on use of ACE inhibitors and angiotensin receptor blockers (ARBs) in hypertensive COVID-19 patients, several clinical findings have recommended their continued use during infection treatment as these drugs possess anti-inflammatory activities as well as inhibit platelets aggregation and thus preventing clot formation seen in COVID-19. Besides synthetic products, some natural products such as amentoflavone, chrysanthemin, and biovobin have shown good binding affinity towards ACE-2 [ 54 , 55 ].

Choroquine (CQ), a well-known anti-malarial drug has been explored for prophylactic and therapeutic treatment in current pandemic due to multiple roles in inhibiting the viral life cycle [ 56 ]. CQ inhibits the viral infection by increasing the endosomal pH value required for the fusion of virus and host cell. Treatment with CQ has shown improved pulmonary abrasion with healthy outcomes. It is also reported that high dose of CQ will cause cardiac risks and its safety and effectiveness is not investigated till now [ [57] , [58] , [59] ]. Hydroxychloroquine (HCQ) shares the similar structure and antiviral activity with CQ and was looked upon as a better and safer treatment for COVID-19. Both are responsible for inhibiting the spike protein attachment with ACE-2 receptor in the host cell and also interfere with the glycosylation process of ACE-2 of host cell. CQ and HCQ decreased the cytokine storm, in COVID 19 patients. It disrupts the DNA/RNA interaction and reduces the expression of pro inflammatory genes [ 60 , 61 ]. However, WHO halted the use of combination of HCQ and lopinavir/ritonavir after their failure to reduce the mortality rate [ 62 , 63 ].

Transmembrane protease serine 2 (TMPRSS2)

Along with ACE-2, TMPRSS2 is also responsible for virus entry into the host cells by activating the viral S-proteins [ 36 ]. TMPRSS2 cuts the S-glycoprotein into two-part S1 and S2. Both subunits function differently; S1 binds with host cell surface receptor and S2 helps in fusion of host and viral cell. It is pertinent to note that spike protein activity is one of the main reasons for the viral pathogenicity and virulence [ 64 ]. Various studies have shown that inactivating the TMPRSS2 could facilitate inhibition of the viral infection. Camostat mesylate is an example of FDA approved serine TMPRSS2 inhibitor used in other diseases, and is under clinical trials for COVID-19 and will take several months for clinical validation [ 65 ].

RNA dependent RNA polymerase (RdRp)

Nsp12 or RdRp is the main conserved protein present in coronavirus which is responsible for viral replication and transcription. It is a complex machinery, where Nsp12 binds with nsp7 and nsp8 (cofactors) to produce viral genomic RNA [ 66 ]. SARS-CoV shares the same structure of Nsp12 with the SARS-CoV-2. It was observed that Nsp12 was the potential drug target with much safer profile and less toxicity for SARS-CoV and MERS-CoV [ 52 ]. Currently, remdesivir (antiviral drug) that targets RdRp activity is under clinical trial and also been used in severely ill-terminal COVID19 patients [ 67 ]. Docking-based screening studies have found some natural compounds targeting RdRp including nympholide A, viniferin and theaflavin [ 55 , 68 ].

3CL protease

Main protease Nsp5, is also known as 3C like protease which first auto cleaved from the poly proteins and then thereafter cleaves the nsps at 11 sites, i.e., nsp4-nsp16, an essential step in the mechanism of viral infection [ 69 ]. This is the main protease hence sometimes called as Mpro and it shares almost 96% homology with SARS-CoV. Difference in structure arises in the dimer interface where polar amino group is replaced with nonpolar groups and hence catalytic activity of dimer increases [ 70 ]. MPro is responsible for viral replication and transcription and considered as an important therapeutic target for COVID-19 [ 71 ]. A combination strategy using lopinavir-ritonavir; the protease inhibitors was tested against COVID-19, however no benefits was observed and it was observed to cause several side effects like diarrhoea, nausea, asthenia etc., but in some regions of South Korea, this combination was found to be effective, however the testing was done only in one patient [ 72 , 73 ]. Thus, clinical study with large cohort of population is needed to establish the importance of this protease as drug target for COVID19.

Papain-like proteinase (PLpro)

PLpro is a 213 kDa multidomain polypeptide which cleaves the N -terminal region of polyprotein and releases nsp1, nsp2 and nsp3 required for correction of viral replication. Along with having role in viral replication, it has other important functions of stripping ubiquitin, deISGylation from proteins of host cell for viral immune evasion processes [ 74 ]. It is also considered as a promising therapeutic target that not only inhibits viral replication but also saves other cells from being infected by dysregulation of signalling cascades in the infected cells. There is a list of FDA approved drugs for various other diseases that specifically binds with viral PLpro effectively, as observed by virtual screening, however needs in vitro, in vivo and clinical validation to establish their effectiveness and clinical use [ 75 , 76 ].

Cathepsin

Like viral protein processing, cellular machinery of virus is also very important and could be a potential therapeutic target [ 77 ]. Keeping in view that SARS-CoV-2 shares similar viral entry mechanism with SARS-CoV, hence similarities in their cellular machinery such as endocytic mechanism for entering into cell could been visaged. Cathepsin is the lysosomal protease that has role in cellular protein turnover [ 78 ]. According to various studies, cathepsin B has important role in life cycles of coronavirus, Nipah virus, Ebola virus, influenza virus etc., and helps the virus to enter into cytoplasm through endosomes by fusing with viral envelope and endosomal membrane [ 79 ]. The most common pathway of viral internalization is clathrin mediated endocytosis as seen in the life cycles of various viruses including coronavirus [ 80 , 81 ]. Cathepsin L is also a promising target in coronavirus as proved by different studies, and therefore it could be a beneficial target for inhibiting SARS-CoV-2. Drug chlorpromazine is used to inhibit clathrin mediated endocytosis in Ebola virus and is being tested for SARS-CoV-2 too [ 82 ]. There are several other drugs available to target cathepsin but so far, all are under clinical trials [ 83 ].

Table 2 summarizes the various repurposed drugs alongwith their SARS-CoV-2 therapeutic targets. Table 2 List of repurposed drugs under clinical trial for COVID-19. Table 2 Drugs Type Target Status Refs. Camostat mesylate Serine protease inhibitor TMPRSS2 Under phase 1 and 2 of clinical trials [ 73 ] Nafamostat mesylate Serine protease inhibitor TMPRSS2 Under phase 2 and 3 of clinical trials [ 73 ] Chloroquine phosphate Antimalarial ACE-2 Under phase 2 of clinical trials [ 73 ] Hydroxy-chloroquine Antimalarial Endosome, pH elevation Still in Controversy [ 73 ] Remdesivir Antiviral RdRp Under clinical trials [ 73 ] Umifenovir Antiviral Membrane fusion, clathrin-mediated endocytosis Under phase 4 of clinical trials [ 73 ] Favipiravir Antiviral RdRp Inconsistent results in clinical trials [ 73 ] Lopinavir Protease inhibitor 3clpro, plpro Inconsistent results in clinical trials [ 63 ] Ribavirin Antiviral RdRp Under phase 3 of clinical trials [ 63 ] Arbidol Antiviral ACE2 Under clinical trials [ 63 ] Baricitinib Rheumatoid arthritis JAK kinase Under clinical trials [ 63 ] Ritonavir Antiviral Protease inhibitor Inconsistent results in completed clinical trials [ 61 ] EIDD-2801 Antiviral Viral replication Prepared for clinical trials [ 61 ] Tociliczumab mAb IL-6 pathway Under phase 3 of clinical trials [ 61 ] Sarilumab mAb IL-6 pathway Under phase 3 of clinical trials [ 61 ] Bevacizumab mAb VEGF pathway Under clinical trials [ 61 ] Vitamin C Dietary supplements Boost immunity Under phase 2 of clinical trials [ 61 ] Vitamin D Dietary supplements Boost immunity Under phase 2 of clinical trials [ 61 ] Azithromycin Antibiotic mRNA translation Under phase 4 of clinical trials [ 61 ] Corticosteroids Corticosteroids Dampen pro-inflammatory cytokines and possess antifibrotic property Still in controversy [ 61 ] Clevudine Antiviral Blocks DNA supply of virus to nucleus Under phase 2 of clinical trials [ 13 ] Isotretinoin Retinoid Against PLPro Under phase 3 of clinical trials [ 13 ] Ivermectin and Nitazoxanide Antiparasitic Inhibit import in alpha/beta receptor Under phase 2 and 3 of clinical trials [ 13 ] Deferoxamine Chelating agents Inhibit IL6 synthesis through decreasing NF-Kb. Under phase 1 and 2 of clinical trials [ 13 ] Dexamethasone Steroid Anti-inflammatory action Under phase 4 of clinical trials [ 13 ] Piclidenoson A3 adenosine receptor agonist Inhibit cytokine storm Under phase 2 of clinical trials [ 13 ] Tranexamic acid Antifibrinolytics Inhibit conversion of plasminogen to plasmin Under phase 2 of clinical trials [ 13 ] BLD-2660 Antiviral Targets IL6 Under phase 2 of clinical trials [ 13 ] Sildenafil citrate Phospho-diesterase inhibitor Dilates blood vessles Under phase 3 of clinical trials [ 13 ] Losartan Angiotensin II receptor antagonist Targets ACE2 Under phase 1 of clinical trials [ 13 ] Telmisartan Antifibrotic Angiotensin receptor blocker Under phase 2 of clinical trials [ 13 ] Atorvastatin Statin Target NF-kB Under phase 2 of clinical trials [ 13 ] Prazosin Alpha-blockers Prevent cytokine storm Under phase 2 of clinical trials [ 13 ] Chlorpromazine Antipsychotics Inhibit viral replication Under phase 3 of clinical trials [ 13 ] Lenalidomide Antiangiogenic agent For multiple myeloma patients Under phase 4 of clinical trials [ 13 ] Ruxolitinib Anti-inflammatory Targets cytokine storm Under phase 3 of clinical trials [ 13 ]

Therapeutic potential of phytoconstituents against coronaviruses

During this pervasive situation, world is facing unhealthy circumstances impeding the normal lifestyle. It is very much necessary to develop drugs or vaccine for this current deadly infectious disease at the earliest, but unfortunately there are no FDA approved drugs available in the market and development of new therapeutic moieties and vaccine remains a costly and time-consuming affair with high failure chances too [ 12 ]. Keeping that in mind it is very crucial to use alternate options to combat the current situation. Medicinal plants offer the most common treatment options since ancient times against various viral diseases because of their safer, cheaper and less toxicity profile [ 84 ]. The National Health Commission of China suggested traditional Chinese medicine as an alternative defence treatment option [ 85 ]. From literature studies it was seen that phytoconstituents such as polysaccharides, triterpenes, phenolic acids, alkaloids, proanthocyanidins and anthraquinones etc., possessed anti-viral activity against rabies virus, HIV, Chandipura virus, Japanese Encephalitis Virus, Enterovirus, Influenza A/H1N1 and other influenza viruses, and SARS [ [86] , [87] , [88] , [89] ]. Table 3 encompasses a list of different phytoconstituents which have shown anti-viral activity against different types of coronaviruses. Table 3 Phytoconstituents and their plant sources having antiviral potential against different types of coronaviruses. Table 3 Compound (source) Structure Strain Targets Refs. Flavonoids Luteolin ( Galla Chinensis ) Image 1 SARS-CoV BJ01 Binds with S2 subunit [ 90 ] Myricetin Image 2 SARS-CoV Inhibit ATPase activity [ 91 ] Procyanidin A2 ( Cinnamomi sp. ) Image 3 SARS-CoV PUMC01 F5 Targets clathrin dependent endocytosis pathway [ 92 ] Scutellarein ( Scutellaria barbata ) Image 4 SARS-CoV Inhibit ATPase activity [ 11 ] Amentoflavone ( Torreya nucifera ) Image 5 SARS-CoV Targets CLPro [ 93 ] Bilobetin ( Torreya nucifera ) Image 6 SARS-CoV Targets CLPro [ 93 ] Ginkgetin ( Torreya nucifera ) Image 7 SARS-CoV Targets CLPro [ 93 ] Bavachinin ( Psoralea corylifolia ) Image 8 SARS-CoV Targets PL Pro [ 94 ] Neobavaisoflavone ( Psoralea corylifolia ) Image 9 SARS-CoV Targets PL Pro [ 94 ] Tomentin A ( Paulownia tomentosa ) Image 10 SARS-CoV Inhibits PL Pro [ 95 ] Tomentin B ( Paulownia tomentosa ) Image 11 SARS-CoV Inhibits PL Pro [ 95 ] Tomentin C ( Paulownia tomentosa ) Image 12 SARS-CoV Inhibits PL Pro [ 95 ] Tomentin D ( Paulownia tomentosa ) Image 13 SARS-CoV Inhibits PL Pro [ 95 ] Tomentin E ( Paulownia tomentosa ) Image 14 SARS-CoV Inhibits PL Pro [ 95 ] Hesperetin Image 15 SARS CoV Against 3CL Pro [ 96 ] Phenolic compounds Kazinol F ( Broussonetia papyrifera ) Image 16 MERS-CoV Targets PL pro [ 97 ] Broussochalcone A ( Broussonetia papyrifera ) Image 17 MERS-CoV Targets PL pro [ 97 ] Caffeic acid ( Sambucus formosana ) Image 18 HCoV-NL63 Inhibit cell docking [ 11 ] Isotheaflavin-3-gallate ( Camellia sinensis ) Image 19 SARS-CoV1 Against 3CL Pro [ 98 ] Dieckol ( Ecklonia cava ) Image 20 SARS CoV Against 3CL Pro [ 99 ] Terrestrimine ( Tribulus terrestris ) Image 21 SARS CoV Against PL Pro [ 100 ] Xanthones Blanco-xanthone ( Calophyllum blancoi ) Image 22 HCoV 229E Against Protease [ 101 ] Pyrano-jacareubin ( Calophyllum blancoi ) Image 23 HCoV 229E Against Protease [ 101 ] Anthraquinones Emodin ( Rheum officinale ) Image 24 SARS-CoV Inhibit binding of S-protein to ACE2 [ 102 ] Coumarins Psoralidin ( Cullen corylifolium ) Image 25 SARS CoV Against PL Pro [ 94 ] Tannins Tannic acid ( Camellia sinensis ) Image 26 SARS- CoV1 Against 3CL Pro [ 16 ] Terpenoids β-Ocimeni ( Laurus nobilis ) Image 27 SARS-CoV FFM1 Inhibit viral replication [ 103 ] β-Penene ( Laurus nobilis ) Image 28 SARS-CoV FFM1 Inhibit viral replication [ 103 ] Tanshinone I ( Salvia miltiorrhiza ) Image 29 SARS-CoV Targets Protease [ 104 ] Tanshinone IIA ( Salvia miltiorrhiza ) Image 30 SARS-CoV Targets Protease [ 104 ] Tanshinone IIB ( Salvia miltiorrhiza ) Image 31 SARS-CoV Targets Protease [ 104 ] Celastrol ( Tripterygium regelii ) Image 32 SARS-CoV Targets protease [ 93 ] Leukamenin ( Lactuca sativa ) Image 33 SARS-CoV1 Protease inhibitor [ 105 ] Glaucocalyxin ( Lactuca sativa ) Image 34 SARS-CoV1 Protease inhibitor [ 105 ] Pseurata ( Lactuca sativa ) Image 35 SARS-CoV1 Protease inhibitor [ 105 ] Pristimerin ( Celastrus orbiculatus ) Image 36 SARS-CoV1 Targets Protease [ 35 ] Tingenone ( Celastrus orbiculatus ) Image 37 SARS-CoV1 Targets 3CL Pro [ 35 ] Iguesterin ( Celastrus orbiculatus ) Image 38 SARS-CoV1 Targets 3CL Pro [ 35 ] Friedelanol ( Euphorbia neriifolia ) Image 39 HCoV-229E Antiviral activity [ 106 ] Friedelin ( Euphorbia neriifolia ) Image 40 HCoV-229E Antiviral activity [ 106 ] Epitaraxerol ( Euphorbia neriifolia ) Image 41 HCoV-229E Antiviral activity [ 106 ] Tingenone ( Tripterygium regeli ) Image 42 SARS CoV Against 3CL Pro [ 93 ] Iguesterin ( Tripterygium regeli ) Image 43 SARS CoV Against 3CL Pro [ 93 ] Pristimererin ( Tripterygium regeli ) Image 44 SARS CoV Against 3CL Pro [ 93 ] Dihydrotanshinone I ( Salvia miltiorrhiza ) Image 45 SARS CoV Against 3 CL Pro and PL Pro [ 107 ] Cryptotanshinone ( Salvia miltiorrhiza ) Image 46 SARS CoV Against 3 CL Pro and PL Pro [ 107 ] Alkaloids Tryptanthrin ( Strobilanthes cusia ) Image 47 HCoV-NL63 Targets papain like protease [ 108 ] Indigodole B ( Strobilanthes cusia ) Image 48 HCoV-NL63 Targets papain like protease [ 108 ] Tetrandrine ( Stephania tetrandra ) Image 49 HCoV-OC43 Inhibit viral replication [ 109 ] Fangchinoline ( Stephania tetrandra ) Image 50 HCoV-OC43 Inhibit viral replication [ 109 ] Cepharanthine ( Stephania tetrandra ) Image 51 HCoV-OC43 Inhibit viral replication [ 109 ] Fatty acids Isolinoleic acid ( Mucuna pruriens ) Image 52 SARS-CoV1 Targets Protease [ 35 ] Steroidal derivatives Saikosaponin B2 ( Bupleurum sp. ) Image 53 HCoV-229E Targets viral replication [ 110 ] β-Sitosterol ( Isatis indigotica ) Image 54 SARS CoV Against 3CL Pro [ 107 ] Flavaglines Silvestrol ( Algaria sp. ) Image 55 MERS-CoV Targets RNA helicase [ 111 ] Glucosides Sinigrin Image 56 SARS CoV Against 3CL Pro [ 107 ] Chalcones Xanthoangelol ( Angelica keiskei ) Image 57 SARS CoV Against 3 CL Pro and PL Pro [ 112 ] Diarylheptanoids Hirsutenone ( Alnus japonica ) Image 58 SARS CoV Against PL Pro [ 113 ] Lectins Agglutinin ( Urtica dioica ) - SARS-CoV Targets viral replication [ 114 ] Griffithsin ( Griffithsia sp. ) - SARS-CoV Against glycoprotein spike [ 115 ]

Various phytoconstituents that are being studied for the treatment of COVID-19 fall under the following classification

Flavonoids

Flavonoids are polyphenolic compounds present in plants and possess different biological functions [ 116 ]. Many flavonoids are seen having effective role against viral infections especially at the molecular level for inhibiting the growth of virus [ 117 ]. Flavonoids block the entry of virus into the cell by blocking the cellular receptors and also interfere with viral replication and translation [ 118 ]. Considering the important role played by Mpro enzyme in viral replication and translation, it can be used as one of the potential targets for COVID-19. Different virtual screening studies carried against Mpro enzyme have proposed several flavonoids like azithromycin, mangiferin, procyanidin-β-2,7-dimethoxyflavaN-4′-O-β- d -glucopyranoside, amentoflavone, hidrosmin, diosmin, gallocathechin gallate, elsamitrucin, pectolinaren, quercetin and isoquercetin having high binding affinities and thus could be used to combat the current situation. Along with the Mpro, ACE-2 is also a potential therapeutic target and flavonoids including hesperetin, myricetin, linebacker and caflanone have shown high binding affinity against ACE-2 making them important points of study against SARS-CoV-2 [ 119 , 120 ].

Alkaloids

Alkaloids are naturally occurring organic compounds containing basic nitrogen atoms [ 121 ]. Alkaloids were found to have key roles in inhibition of viral replication as it blocks the function of viral DNA polymerase [ 122 ]. As these plant's secondary metabolites have DNA intercalating properties, they may be effective candidates against viral infection and could lead to development of drug molecules. Resoquine, synthetic derivative of quinine (alkaloid), an antimalarial drug has been found as an effective therapeutic agent against COVID-19 [ 123 ]. Isoquinoline was effective against spike protein and nucleocapsid protein of SARS-CoV-OC43 in human lung cells suggesting that this could serve as a drug candidate against SARS-CoV-2. Some alkaloids which are having DNA intercalating activity are sanguinarine, quinine, cinchonine, hartmine, chelidonine, coptisine, berberine, palmatin, tetradine etc., and could be used for development of drug molecules [ 124 , 125 ]. Emetine isolated from ipecacuanha root for induction of vomiting in the poisoning management has been found as effective against COVID-19 [ 126 ].

Phenolics

Phenolics are naturally occurring plant polyphenolic compounds having one or more hydroxyl groups which bind with aromatic hydrocarbon group. They possess the chemical properties where hydroxyl group dissociates under various physiological conditions [ 127 ]. Phenolic compounds carrying five or more hydroxyl group along with methoxyl group have antiviral properties [ 128 ]. Plants like Euphorbia spindens and Bombax malabaricium were tested for anti-HSV and anti-RSV respectively and were effective like ribavirin (antiviral) synthetic drugs [ 129 ]. Phenols help in inhibiting the fusion of virus to the host cell by binding with the viral protein present in the viral envelope. Since most of the polyphenols are polar molecules and hence cannot be taken up by the host cells and thus may prove as good candidates against COVID-19 [ 123 , 130 , 131 ].

Essential oils

Essential oils are the volatile concentrated hydrophobic liquids extracted from plants. Essential oils are extensive used in phytomedicine and aromatherapy and also in pharmaceuticals. They possess different biological functions like antibacterial, antifungal, antiviral, antioxidant, anti-inflammatory, anticancer etc. [ 132 ]. Several reports described the effective antiviral activity of essential oils on influenza virus, herpes simplex virus etc. A mixture of essential oil and oleoresins from medicinal plants was also tested for coronavirus, bronchitis virus etc. [ 133 ]. Essential oil easily interacts with phospholipid bilayer of the cell membrane and it disrupt the viral envelope, thus starting their activity prior to host cell attachment.

Lypophillic essential oils work on membrane viral proteins required for fusion but its activity stops once the virus enters inside the cell [ [134] , [135] , [136] , [137] ]. Recently a team of scientists tested cannabis terpenes for antiviral activity against COVID-19 and the terpenes were found to reduce the severity of SARS virus by interruption with RNA replication proteins thus interfering with viral penetration in healthy cells [ 124 ]. Various essential oils have proved to be effective against various types of viruses which includes isoborneol, a monoterpenene, having antiviral effect against HSV1. Similarly, eugenol delayed the growth of Herpes virus and also interferes with HSV, while beta-caryophyllene was found to be effective against dengue virus [ 138 , 139 ]. Vanguard Scientific recently launched an effective hand sanitizer having plant derived terpenes [ 140 ]. Essential oils thus constitute a major group of phytochemicals which are needed to be investigated thoroughly for the finding of new effective treatment against the COVID-19 severity.

Stilbenes

Stilbenes are naturally occurring defensive phenolic compounds found in grapes, berries, bark waste etc., also classified as phytoalexins as they are synthesized by plants in response to UV radiations. Stilbene have many biological functions like antioxidant, anticancer, anti-inflammatory, antileukemia, anti-HIV, anti-Herpes simplex virus, etc. [ 141 , 142 ]. Different virtual screening studies suggested the use of stilbenes in COVID-19 as they inhibit the complex formed between spike protein and ACE-2 receptor by disrupting the interface of S-ACE-2 complex and thus blocking the entry to the host cell. Stilbenes having high binding affinity to this complex include resveratrol and piceatannol. Some other derivatives of stilbenes like trans -resveratrol, pinosylvin, pterostilbene also have antiviral properties but with low binding capacity than mentioned previously [ [143] , [144] , [145] ]. Resveratrol has been already tested for MERS-CoV and was found effective as it decreases the cell death [ 146 ]. Based on these studies, it is suggested that stilbenes derivatives, especially resveratrol could be very important drug candidate for COVID-19.

Glycosides

Glycosides are simple sugar molecules having different functional groups. Different drugs and poisons extracted from plants are glycosides and thus useful in various treatments [ 147 ]. Antiviral effects of glycosides have been observed in various studies like the cardiac glycosides were seen effective against both DNA and RNA viruses including cytomegalo virus, herpes simplex virus, influenza virus and coronavirus [ 148 ]. It targets the cell host protein and thus makes them promising strategy against human viral infections [ 149 ]. It was already seen that glycosides are effective for influenza virus as it interferes with the virus attachment and disturbs the release of new viruses by inhibiting the hemagglutinin and sialidase enzymes [ 150 , 151 ]. Iridoid glycosides from Fructus gardeniae are very much effective against influenza A as it reduced the cell death by suppressing influenza virus replication [ 152 ]. According to a recent report, antiviral activity of Ginsenoside Rb1 class of steroid glycosides was tested and found to be effective against SARS-CoV [ 153 ]. Thus, glycosides derivatives need detailed investigation as drug targets for minimising the current pandemic scenario.

Saponins

Saponins are non-ionic detergents which possess antifungal, cytotoxic, antibacterial and antiviral properties [ 154 ]. Saponins are used in the development of steroidal drugs and thus used in modern medicine [ 155 ]. Saponins carries antiviral activity as it can interact with viral envelope and capsid protein which results into disruption of viral particles, also it can interact with host cell membrane which inhibit the viral particle attachment to the host cells thus prevent fusion by coating the cell surface which minimizes the spreading of infections. Some study found that Quilaja saponaria extract containing triterpenoid saponins having very strong activity in both human and animal's vaccines. This extract was very effective against HIV-1 and -2 [ 156 , 157 ]. Similarly, triterpene saponin from Anagallis arvensis showed antiviral activity against HSV1 and poliovirus 2 [ 158 ]. Saikosaponins are triterpene saponin glycosides that have been reported having effective antiviral activity against coronavirus HCoV-229E. Saikosaponins interfere with the early stage of viral replication including adsorption and penetration. Some studies demonstrated the antiviral activity of saikosaponins on other viruses like herpes simplex virus, hepatitis B virus and cytomegalovirus and HIV [ 110 , 159 ]. Thus, this approach of saponins needs attention of scientists for investigation in detail for the development of effective therapeutic candidate against COVID-19.

Tannins

Tannins are naturally occurring compounds found in plants, seeds, bark, wood and fruits etc. and possess various biological properties and medical uses. The viral infections lead to the overproduction of free radicals and thus oxidative stress triggering the production of reactive oxygen and nitrogen molecules and tannins extracted from plants are very much effective against oxidative stress [ 160 , 161 ]. Several studies confirmed the antioxidant effect as a potential therapy against various viral infections [ 162 ]. Antiviral activity of tannins against various viruses like enterovirus, calicioviruses, rotavirus, HIV, herpes simplex virus, and coronaviruses, etc., has been well established [ 163 ]. Tannins like pedunculagin, tercatainj and punicalin can binds effectively with SARS-CoV-2 which interferes with viral binding site and destroy the protease enzymes such as His41 and Cys145 and this was studied recently by molecular docking methods [ 164 ]. A recent study from India suggested the use of tea and haritaki having therapeutic potential against COVID19 as gallotannin present in tea can interfere with 3CLPro protease activity of coronavirus, but yet clinical trials are not done [ 165 ].

Anthraquinones

Anthraquinones are naturally occurring aromatic compounds having wide range of medicinal applications such as in constipation, arthritis, multiple sclerosis, cancer and others and demonstrate low toxicity with high activity [ 166 , 167 ]. Currently molecular docking studies showed the effect of anthraquinones against SARS-CoV-2. Derivatives such as emodin, aloin A and B, rubiadin, aloe-emodin, pseudohypericin, damnacanthal, and chryosphanic etc., were found as inhibitors of Mpro of SARS-CoV-2 using docking studies. But the detailed in vivo and invitro studies are required to be done to develop promising drug candidate against COVID19 [ [168] , [169] , [170] ]. Emodin extracted from Rheum officinale and Polygonum multiflorum was also able to block the S-protein binding with ACE-2 receptor in SARS coronavirus [ 102 ]. Anthraquinone derivatives such as hypericin are effective against various other viruses like herpes simplex virus, vaccinia virus and parainfluenza virus [ 171 , 172 ].

Various computational tools showed the data of phytoconstituents from different medicinal plants against various therapeutic targets of COVID-19 and thus could be effective against this viral disease. Various types of phytoconstituents investigated through in silico docking studies in the SARS-CoV-2 are listed in Table 4 . Table 4 List of phytoconstituents screened via in silico studies against targets of SARS-CoV-2. Table 4 Compound Structure Source Mechanism Refs. Flavonoids Myricitrin Image 59 Myrica cerifera interacts with 3CLPro [ 173 ] 3,5,7,3′,4′,5′-hexahydroxy flavanone-3-O-beta-D-gluco-pyranoside Image 60 Phaseolus vulgaris protease inhibition [ 173 ] (2S)-Eriodictyol 7-O-(6″-O-galloyl)-beta-D-glucopyranoside Image 61 Phyllanthus emblica protease inhibition [ 173 ] Calceolarioside B Image 62 Fraxinus sieboldiana interact with HIS41 and Cys145 [ 173 ] Kaempferol Image 63 Securigera securidaca PLpro & 3CLpro [ 87 ] Quercetin Image 64 Withania somnifera PLpro & 3CLpro [ 35 , 87 ] Myricetin 3-O-beta-D-glucopyranoside Image 65 Camellia sinensis 3CL Pro inhibition [ 173 ] Licoleafol Image 66 Glycyrrhiza uralensis 3CL Pro inhibition [ 173 ] Taiwan-homoflavone A Image 67 Cephalotaxus wilsoniana Binds with 3CL pro and ACE2 [ 55 ] Afzelin Image 68 3CL Pro inhibition and ACE2 [ 174 ] Isoquercitrin Image 69 3CL Pro inhibition and ACE2 [ 174 ] Amentoflavone Image 70 3CL Pro inhibition and ACE-2 [ 174 ] Nympholide A Image 71 Aquatic plant M pro and RdRp [ 55 ] Biorobin Image 72 Acalypha indica RdRp and hACE-2 [ 55 ] Luteolin-7-glucoside Image 73 Olea europaea L Mpro inhibitor [ 87 ] Naringenin Image 74 Citrus sinensis Mpro inhibitor [ 87 ] Apigenine-7-glucoside Image 75 Averrhoa belimbi Mpro inhibitor [ 87 ] Silybin Image 76 Silybum marianum spike protein inhibition (TMPRSS2) [ 175 ] 5,7-Dimethoxy flavan-4-O-β-D-glucopyranoside Image 77 inhibit Mpro [ 33 ] Baicalin Image 78 binds with TMPRSS2 [ 174 ] Isoflavonoids 5,7,3',4'-Tetrahydroxy-2'-(3,3-dimethylallyl) isoflavone Image 79 Psorothamnus sp. interacts with 3CLPro [ 173 ] Daidzein Image 80 Cicer arietinum Blocks HSPA5 [ 68 ] Genistein Image 81 Cicer arietinum Blocks HSPA5 [ 68 ] Formononetin Image 82 Cicer arietinum Blocks HSPA5 [ 68 ] Biochanin A Image 83 Cicer arietinum Blocks HSPA5 [ 68 ] Nictoflorin Image 84 Nyctanthes arbortristis interact with protease [ 125 ] Terpenoids Betulinic acid Image 85 Chinese medicinal plant replication &3CLpro [ 11 ] Crypto-tanshinone Image 86 Chinese medicinal Plant PLpro & 3CLpro [ 11 ] Dihydro-tanshinone Image 87 Chinese medicinal Plant entry & spike protein [ 11 ] Sugiol Image 88 Chinese medicinal Plant Replication & 3CLpro [ 11 ] Tanshinone IIA Image 89 Chinese medicinal plant PLpro & 3CLpro [ 11 ] Nimolicinol Image 90 Azadirachta indica protease inhibition [ 35 ] Lactucopicrin Image 91 Lactuca virosa 3CL Pro inhibition and ACE2 [ 55 ] Cordioside Image 92 Tinospora cordifolia binds with main protease [ 175 ] Vindolinine Image 93 Catharanthus roseus binds with NSP15 [ 35 ] Camphorating D Image 94 Cinnamomum verum blocking signalling pathway [ 169 ] Bonducellpin D Image 95 inhibit Mpro Gurung et al., 2020 Nimbin Image 96 Azadirachta indica Interact with protease [ 33 ] Alkaloids Desmethoxy-reserpine Image 97 Chinese medicinal Plant Replication, 3CLpro & entry [ 11 ] Moupinamide Image 98 Piper nigru PLpro [ 11 ] Amaranthin Image 99 Amaranthus tricolor 3CL Pro inhibition [ 173 ] Oriciacridone F Image 100 binds with 3CL and ACE2 [ 174 ] Somniferine Image 101 Withania somnifera binds with NSP15 [ 35 ] 2,3-Dehydro-somnifericin Image 102 Withania somnifera binds with NSP3 [ 35 ] Anaferine Image 103 Withania somnifera binds with NSP10, NSP16 [ 35 ] Berberine Image 104 Tinospora cordifolia interact with protease [ 125 ] Phenolic compounds Theaflavin Image 105 Camellia sinensis binds with RdRp [ 11 ] Methyl rosmarinate Image 106 Hyptis atrorubens interacts with 3CLPro [ 173 ] Coumaroyl-tyramine Image 107 Chinese medicinal Plant PLpro & 3CLpro [ 11 ] Lignan Image 108 Chinese medicinal Plant replication & 3CLpro [ 11 ] Demethoxy-curcumin Image 109 Curcuma longa Mpro inhibitor [ 87 ] Aloenin Image 110 Aloe Vera interact with protease [ 125 ] Gingerol Image 111 Zingiber officinale Interact with protease [ 125 ] Steroidal compounds 27-Deoxy-14- hydroxy withaferin A Image 112 Withania somnifera protease inhibition [ 35 ] 27-Hydroxy withanone Image 113 Withania somnifera interferes with Spike protein [ 35 ] 12-Deoxy witha-stramonolide Image 114 Withania somnifera interferes with Spike protein and binds with NSP9 [ 35 ] 27-Deoxy withaferin A Image 115 Withania somnifera interferes with Spike protein [ 35 ] 2,3-Dihydro withaferin A Image 116 Withania somnifera interfers with Spike [ 35 ] 27-Hydroxy withanolide B Image 117 Withania somnifera binds with NSP10 [ 35 ] Witha-stramonolide Image 118 Withania somnifera binds with NSP12 D2 [ 35 ] Withanolide B Image 119 Withania somnifera binds with NSP12 D2 and binds with NSP3 [ 35 ] Withanolide R Image 120 Withania somnifera binds with NSP12 D2 [ 35 ] Withaferin A Image 121 Withania somnifera binds with NSP12 D2 [ 35 ] 27-Hydroxy withanolide B Image 122 Withania somnifera binds with NSP9 [ 35 ] Aza-diradionolide Image 123 Azadirachta indica binds with NSP9 [ 35 ] 27-Deoxy-14-hydroxyl withaferin A Image 124 Withania somnifera binds with NSP3 [ 35 ] Anthraquinones Microcarpin Image 125 binds with TMPRSS2 [ 174 ] Anthocyanins Chry-santhemin Image 126 Black grapes RdRp and hACE-2 [ 55 ] Stilbenes δ-Viniferin Image 127 Grapevine leaves M Pro , RdRp and hACE-2 [ 55 ] Iso-gemichalcone Image 128 binds with TMPRSS2 [ 174 ] Lactones Limonin Image 129 Nigella sativa binds with NSP16 [ 35 ] Durumolide K Image 130 binds with TMPRSS2 [ 174 ] Fatty acids Dihomo-gamma-linolenic acid Image 131 Chinese medicinal plant 3CLpro [ 11 ] Phthalates Solvanol Image 132 Solanum nigrum binds with NSP16 [ 35 ]

Conclusions

In current adverse conditions of COVID-19 across the world, it is the urgent need of time to develop drugs or therapeutic options at the earliest. Developing new drugs and identifying novel drug targets are indeed time consuming and validation of such novel drugs/targets in clinical trials are mandatory to check their efficacy and effectiveness. Unavailability of the drugs and specific treatments for COVID-19 till date motivate the researchers to look for alternatives for successfully combating the current disease scenario. In this regard, medicinal plants containing specific phytomoieties could provide a wide scope as therapeutic drugs against COVID-19. Furthermore, the low toxicity of herbal medicines and an easy development process provide additional advantages in their fast and wide usage. This study has compiled a data of different types of phytoconstituents possessing antiviral activity against Coronaviruses as well as phytoconstituents showing affinities against therapeutic targets of SARS-CoV-2 like RdRP, 3CLpro, PLpro and the host cell targets like ACE-2 based on the computational screening methods. However, further in vivo and in vitro studies need to be done to confirm the bioactivity of these compounds against COVID-19. Overall, the development of phytopharmaceuticals as an alternative approach could be seen as a viable treatment option against SARS-CoV-2 in current COVID-19 pandemic.

Funding information

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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