Introduction

Among the two coronavirus subtypes (alpha and beta), beta coronavirus has been reported to be the major cause of three pathogenic zoonotic disease outbreaks over the last two decades. Severe acute respiratory syndrome coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), and coronavirus disease 2019 (COVID-19) were epidemics in 2002, 2012, and 2019 [1]. COVID-19 caused havoc and damage to the world population and is a global threat in the twenty-first century [2]. This pandemic outbreak of COVID-19 will forever remain an unprecedented epidemic in the history of mankind [3]. As of April 20, 2022, the World Health Organization (WHO) had received reports of 504,079,039 confirmed COVID-19 cases worldwide, with reported deaths accounting for 6,204,155 [4]. Even though the race for eradicating the virus has been in extreme progress with the emergence of novel COVID-19 vaccines, biotechnological products, and antiviral drugs, however, scientists from all over the world are still trying to research the best possible diagnostic methods to put an end to this deadly pandemic.

Plants have been a source of medicine and food for ages [5, 6]. Around 80% of the world’s population still relies on plants for their health [7]. Metabolites of the plant can be a potent source of alternative therapy for COVID-19 treatment [8]. In silico studies can be useful therapeutic tools to discover novel molecules as potential inhibitors of SARS-CoV-2, and this can be purpose by screening the binding efficacy of the plants’ secondary metabolites against the active sites of the target proteins. Hence, the present review aims to specifically report the importance of in silico studies taking into account the binding efficacy of the active phytochemical compounds (isolated from plants) towards the active sites of SARS-CoV-2.

Methodology

The systematic review was performed as per PRISMA guidelines [9]. A literature survey was performed in “PubMed” using the indexed term (in-silico studies, phytoconstituents, and SARS-CoV-2) separated by Boolean operators (“AND” and “OR”), and a total of 233 articles were obtained. All the research articles and reviews published until February 7, 2022, were considered for the study. Exclusion criteria omitted from the investigation were in silico data for semi-synthetic derivatives and plant extracts. The phytoconstituents obtained from the review were further determined for their drug-likeness using the Molsoft database (www.molsoft.com/mprop/).

Results

Potential protein targets of SARS-CoV-2

The genome of SARS-CoV-2 consists of a 5′ untranslated region, which includes a 5′ leader sequence; an open reading frame encoding non-structural proteins; four structural proteins, which include spike (S), envelope (E), membrane (M), and nucleocapsid (N); several accessory proteins; and a 3′ untranslated region as shown in Fig. 1 [10]. These proteins can be targeted and used to develop a new drug. The protein targets of SARS-CoV-2 are explained in the following subsections for a better understanding of the drug effect.

Fig. 1
figure 1

Different binding epitopes for a drug target sites of SARS-CoV-2

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Spike glycoprotein of SARS-CoV-2

The spike glycoprotein is the only structural protein responsible for the SARS- “crown”-like-CoV-2’s structure; hence, the moniker “coronavirus” was coined. It is a transmembrane protein located in the outer region of the virus. The attachment of the spike glycoprotein to the host cell angiotensin-converting enzyme-2 receptor (ACE-2) is the first step in getting CoV into the host cells. The type II transmembrane serine protease on the host cell’s surface clears ACE-2 and activates the receptor connected to spike-like S proteins. Virus entrance into cells is enabled by the conformational change that happens after activation. As a result, both type II transmembrane serine protease and ACE-2 are essential for viral entry. Homotrimers are generated when S protein protrudes from the viral surface, allowing enveloped viruses to adhere to host cells through ACE-2 attraction [10]. The cleavage of spike protein using proteases produces two subunits S1 and S2. Both the units play a major role in recognizing receptors and membrane fusion. Moreover, S1 is further divided into two important domains—the N-terminal domain and the C-terminal domain. The S1 C-terminal domain shows a higher affinity to bind with the ACE-2 receptor, contrary to the N-terminal domain. The receptor-binding domain of SARS-CoV-2 has been discovered to be the major area interacting with human ACE-2 [11]. The fusion peptide, a secondary proteolytic site, two heptad-repeat domains preceding the transmembrane domain, and an internal fusion peptide make up the S2 subunit. ACE2 is highly expressed in nasal epithelial cells, goblet/secretory cells, and ciliated cells, in addition to being found in many organs such as the heart, kidney, and gastrointestinal tract. Inside the host, the virus releases its subsequent genomic material, mRNA, in the cytoplasm and gets translated, thereby generating polyproteins, namely, pp1a and pp1b. These replicase polyproteins are further cleaved by virus-encoded proteinases into small proteins. Furthermore, ribosomal frameshifting occurs during the entire translation process, creating both genomic and multiple copies of subgenomic RNA species through discontinuous transcription encoding for important viral proteins. The viral RNA and protein interaction construct the virion, which is later discharged from the cells through the vesicles [12].

Membrane (M) protein of SARS-CoV-2

In the CoV particle, the M glycoprotein is the most abundant protein. It has 230 amino acids and three key parts—an N-terminal domain placed outside the virion membrane, three transmembrane domains, and a carboxy-terminal domain located inside the virus particle. In the virion, it occurs as a dimer with two conformations-long and compact (MLONG and MCOMPACT), which cause membrane curvature and nucleocapsid binding when coupled. M glycoprotein can enhance curvature before attaching to the nucleocapsid in a variety of ways. Furthermore, in alpha- and gamma-coronaviruses, N-linked glycosylation is common, whereas, in beta-coronaviruses, the common is O-linked glycosylation [13]. Reverse genetic studies have suggested that M glycoprotein promotes assembly by interacting with viral ribonucleoprotein and S glycoproteins at the budding site. It also forms a network of M-M interactions capable of preventing some host membrane proteins from interacting with the virus envelope. The protein plays a key role in virus assembly, where cellular membranes are transformed into workshops and the virus, together with host components, is gathered to produce new virus particles. M proteins interact through both the transmembrane domain and the endodomain. There is less evidence of detailed structure and functional information because of its tiny size, intimate interaction with the viral envelope, and tendency to form insoluble aggregate [14]. M protein’s versatility is achieved through interactions with S, N, and E proteins. The interaction of S with M protein is required for the retention of S in the endoplasmic reticulum-Golgi intermediate compartment/Golgi complex and its integration into new virions. Furthermore, the interaction of M with N-protein stabilizes the N-protein and RNA complex, followed by the internal core of virions. In addition, the binding aids in the completion of viral assembly. Finally, the viral envelope is formed by the interaction of M with E protein, which is sufficient for both the synthesis and release of virus-like particles [15].

Envelope (E) protein of SARS-CoV-2

The envelope protein (E protein) is one of the smallest proteins compared to other proteins comprising 79–106 amino acids. Its size ranges from 8.4 to 12 kDa and consists of two structural domains: a large hydrophobic domain containing 25 amino acid residues and a hydrophilic carboxyl terminus that forms most of the protein [15]. The bizarre long hydrophobic stretch containing 25–30 amino acid residues is placed in between the hydrophilic N- and C-terminus [16]. The C-terminus is exposed to the cytoplasmic side, while the N-terminus is translocated across the membrane. An even-net charge distribution was discovered on both sides of the E-protein membrane. Only eight charged residues have been discovered in the protein sequence: two negatively charged residues preceding the transmembrane section, five charged residues, and one negatively charged residue in the C-terminal domain [17]. Interestingly during the replication cycle, only a few portions are assimilated into the virion envelope, and on the contrary, the protein is mostly expressed inside the infected cell [15]. Apart from the assembly of virions, E protein also plays an emerging role in virus entry, followed by the host stress response. The protein interacts with host proteins through ion channel activity leading to the study of topologies of multiple membranes [18]. Moreover, depending on the genus of the virus, the need for E protein varies for the morphogenesis of the virus. The production of the virus is significantly compromised to approximately 1000-fold in the absence of envelope protein, thereby implementing that the protein plays an emerging role during morphogenesis [19]. The interaction between two proteins—E and M—is primarily essential for the budding process in pre-Golgi compartments, where the interlink of two proteins occurs because of cytoplasmic domains. The morphology of the Golgi apparatus is changed dramatically during the expression of E and thus explaining the importance of protein in inducing apoptosis. Incorporation into vesicles results because of the expression of protein alone, thereby promoting it to release from cells and the assembly of CoV-like particles is formed due to co-expression of the E protein with the other protein, namely, M, membrane protein [16].

Nucleocapsid protein of SARS-CoV-2

The CoV nucleocapsid protein is the most stable substructure of the viral particle composed of a thread-like strand, 8–9 mm in diameter, coiled or helical superstructure budding into the endoplasmic reticulum of infected cells. It is fairly flexible and almost shows the similarity of the structure with paramyxovirus nucleocapsids [20]. Aside from transcription and replication, the N protein is involved in the creation of helical ribonucleoproteins when the RNA genome is packed, as well as viral RNA synthesis regulation and infected cell metabolic modulation. Its architecture consists of three domains, namely, N-terminal RNA-binding domain (NTD) responsible for RNA binding, a C-terminal dimerization domain for oligomerization, and a central Ser/Arg (SR)-rich linker required for phosphorylation [21]. Moreover, being resolved by SDS-PAGE, the virion-associated-N protein of CoV was considered a single species of molecular weight ranging from 45–63 kDa depending upon the virus and strain. The protein is highly basic in that lysine and arginine amino acids predominate over aspartate and glutamate residues, accompanied by relatively high serine content (7–11%) [20]. The middle of the C-terminal region is essential for the antibodies to be elicited against SARS-CoV-2 during the immune response [22]. The primary characteristic that distinguishes N protein from other structural proteins is that it regulates the interlink of host and pathogen, such as reorganization of actin, progression of the host cell cycle, and apoptosis [21].

In silico molecular docking activity of active natural phytoconstituents against SARS-CoV-2

One of the well-known in silico methods for predicting the interlink between molecules and biological targets is molecular docking. This is accomplished by calculating a ligand’s molecular familiarization with a receptor and then calculating its correlation using a docking score [23]. Different phytoconstituents demonstrated varying levels of binding effectiveness with SARS-CoV-2 targets. Interestingly, several phytoconstituents were found to have the ability to bind to numerous proteins. The literature review found that 100 phytoconstituents act on different targets of SARS-CoV-2. The list of the phytoconstituents is shown in Table 1. Table 2 enlists the binding probability of distinct classes of phytochemicals against different SARS-CoV-2 site proteins. Some of the phytoconstituents that show better stability with targets of SARS-CoV-2 based on their binding energy are shown in Table 3.

Table 1 In silico reports on the binding efficacy of various active phytoconstituents against SARS-CoV-2 protein/enzyme
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Table 2 Binding probability of diverse classes of phytochemicals against different site proteins of SARS-CoV-2
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Table 3 Phytoconstituents showing better stability with targets of SARS-CoV-2 based on their binding energy
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Binding affinity of phytoconstituents with Spike glycoprotein of SARS-CoV-2

The result achieved from the current review revealed that 23 was found to act on spike glycoprotein. Based on the available data reported in this review, the docking score of curcumin (− 115.198 kcal/mol) was found to be quite impressive followed by apigenin (− 108.614 kcal/mol), chrysophanol (− 107.385 kcal/mol), emodin (− 105.462 kcal/mol), zingerone (− 102.18 kcal/mol), gingerol (− 98.03 kcal/mol), and epigallocatechin gallate (− 91.72 kcal/mol) [24]. The chemical structure of some of the phytoconstituents inhibiting spike glycoprotein with superior binding energy is shown in Fig. 2. Contrary to our findings, the data reported in the literature revealed that some of the Food and Drug Administration (FDA)–approved drugs for SARS-CoV-2-like ivermectin, doxycycline, hydroxychloroquine, azithromycin, remdesivir, and oseltamivir also inhibited the spike glycoprotein with promising binding energies: − 102.63 kcal/mol, − 77.46 kcal/mol, − 69.19 kcal/mol, − 90.34 kcal/mol, − 83.36 kcal/mol, and − 81.45 kcal/mol, respectively [25]. This depicted that phytoconstituents may play an equal and significant role as FDA-approved drugs in the management of COVID-19 infections. Even though such compounds have shown potential binding efficacy as predicted by virtual in silico studies, there are still research gaps in which none of the phytoconstituents has been investigated for their efficacy against SARS-CoV-2. As a result, new preclinical and clinical initiatives are necessary to close this research gap.

Fig. 2
figure 2

Phytoconstituents inhibiting spike glycoprotein and their binding energy

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Binding affinity of phytoconstituents with M.pro of SARS-CoV-2

Findings from the current review revealed that 77 phytoconstituents targeted the active sites of the Mpro. Some of the phytoconstituents with promising binding efficacy include laurolistine with a docking score of − 294.15 kcal/mol, acetoside (− 11.97 kcal/mol); cryptoquindoline (− 9.70 kcal/mol); avicularin (− 9.6 kcal/mol); cryptospirolepine (− 9.2 kcal/mol); astragalin (− 9.12 kcal/mol); and calendoflaside (− 8.5 kcal/mol) [26,27,28,29,30]. Eventually, data which are available in the literature revealed that some synthetic drugs that showed promising role against SARS-CoV-2 by inhibiting Mpro are carfilzomib (− 13.8 kcal/mol), azithromycin (− 8.2 kcal/mol), chloroquine (− 7.9 kcal/mol), hydroxychloroquine (− 6.5 kcal/mol), streptomycin (− 3.8 kcal/mol), and ribavirin (− 2.01 kcal/mol) [31]. Contrary to our findings, it can be predicted that the phytoconstituents reported in this current review may also show a promising role against SARS-CoV-2 inhibition, as compared to that of the synthetic ones. However, as mentioned in the earlier statement, there is a lack of research in in vivo models which may be regarded as a research gap and need to be evaluated further. However, a further check-in drug-likeness for calendoflaside using the Molsoft database (www.molsoft.com/mprop/) suggested that there were three penalties of Lipin’s key rule of 5 with molecular weight, 608.17 (> 500); number of hydrogen bond acceptor (HBA), 15 (> 10); and number of hydrogen bond donor (HBD), 8(> 5). Cryptospirolepine has two penalties with molecular weight 504.20 (> 500) and mol LogP 5.98 (> 5). Acetoside showed three penalties with molecular weight, 624.21(> 500); number of HBA, 15(> 10); and number of HBD, 9(> 5). The above findings show a major research gap with no studies designed to enhance the drug-likeness of the above phytoconstituents. A chemical modification can be done on acetoside, cryptospirolepine, and calenoflaside to eliminate the drug-likeness penalties. Hence, it can be inferred that laurolistine, avicularin, astragalin, and cryptoquindoline (Fig. 3) can be potent phytoconstituents against SARS-CoV-2 by inhibiting Mpro.

Fig. 3
figure 3

Phytoconstituents inhibiting Mpro and their binding energy

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Binding affinity of phytoconstituents with ACE-2 of host cell receptor

A total of 6 phytoconstituents were found to act on the ACE-2 target. Out of which, absinthin has the docking score of − 11.8 kcal/mol followed by 3,5-di-O-galloylshikimic acid (− 10 kcal/mol), scutellarein 7-glucoside (− 9.3 kcal/mol), avicularin (− 8.0 kcal/mol), cirsimaritin (− 7.2 kcal/mol), and hispidulin (− 7.3 kcal/mol) [30, 32, 33]. Some of the synthetic drugs targeting ACE-2 in host cells are azithromycin (− 10.5 kcal/mol), hydroxychloroquine (− 8.5 kcal/mol), and chloroquine (− 4.2 kcal/mol) [31]. This implies that absinthin, 3,5-di-O-galloylshikimic acid, scutellarein 7-glucoside, avicularin, cirsimaritin, and hispidulin have a nearly identical binding score to the synthetic medication that targets ACE-2. It is possible that such phytoconstituents may demonstrate the promising binding activity with ACE-2 and hence will play a role in SARS-CoV-2 suppression. However, a check-in drug-likeness for scutellarein 7-glucoside using the Molsoft database (www.molsoft.com/mprop/) suggested that there were two penalties of Lipin’s key rule of 5 with a number of HBA 11(> 10) and number of HBD 7(> 5). On the other hand, there was no preclinical or clinical study conducted on absinthin, 3,5-di-O-galloylshikimic acid, avicularin, cirsimaritin, and hispidulin to determine its effect on SARS-CoV-2 creating a major gap in research. The structure of phytoconstituents inhibiting ACE-2 and with no penalties of Lipin’s key rule of 5 is shown in Fig. 4.

Fig. 4
figure 4

Phytoconstituents inhibiting ACE-2 and their binding energy

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Binding affinity of phytoconstituents with RdRp

Some of the synthetic drugs that inhibit the enzyme RdRp with best binding energy are raltegravir (− 9.5 kcal/mol), doxazosin (− 9.3 kcal/mol), tadalafil (− 9.2 kcal/mol), and ceftriaxone (− 9.0 kcal/mol) [34]. According to the current review, one phytoconstituent, namely, asparoside-C binds to RdRp with a binding energy of − 6.65 kcal/mol [35]. Moreover, a check-in drug-likeness for asparoside-C using the Molsoft database (www.molsoft.com/mprop/) suggested that there were 3 penalties of Lipin’s key rule of 5 with molecular weight 1212.61 (> 500), a number of HBA 27 (> 10), and number of HBD 15 (> 5). However, asparoside-C can still be chemically modified to get rid of the penalties of Lipin’s key rule of 5 and approached for further studies to treat SARS-CoV-2.

Binding affinity of phytoconstituents with receptor binding domain of spike protein (S-RBD)

The phytoconstituents that bind to S-RBD are asparoside-C (− 7.16 kcal/mol), asparoside-D (− 7.06 kcal/mol), and shatavarin-I (− 6.52 kcal/mol) [35]. Literature reports that some well-known synthetic drugs that bind to S-RBD are azithromycin (− 7.0 kcal/mol), chloroquine (− 4.2 kcal/mol), and hydroxychloroquine (− 4.9 kcal/mol) [31]. This suggests that asparoside-C, asparoside-D, and shatavarin-I probably have similar binding energy when compared to the synthetic drug. However, a check-in drug-likeness for asparoside-C using the Molsoft database (www.molsoft.com/mprop/) suggested that there were three penalties of Lipin’s key rule of 5 with molecular weight 1212.61 (> 500), number of HBA 27 (> 10), and number of HBD 15 (> 5). Asparoside-D showed three penalties with molecular weight 1198.60 (> 500), number of HBA 27 (> 10), and number of HBD: 16 (> 5). Similarly, Shatavarin-I also showed 3 penalties of Lipin’s key rule of 5 with molecular weight 1066.56 (> 500), number of HBA 23 (> 10), and number of HBD 14 (> 5). Therefore, all three phytoconstituents must be chemically modified in the future for further studies to treat SARS-CoV-2.

Binding affinity of phytoconstituents with E protein

As per the literature, we found 3 phytoconstituents that act on the E protein target, viz., belachinal (− 11.46 kcal/mol), macaflavanone E (− 11.07 kcal/mol), and vibsanol B (− 11.01 kcal/mol) [36]. Moreover, some of the synthetic antiviral drugs that bind to E protein include glecaprevir (− 11.8 kcal/mol), saquinavir (− 10.7 kcal/mol), and simeprevir (− 11.3 kcal/mol) [37]. This suggests that belachinal binding energy towards E protein is more or less similar to that of the reported synthetic drugs. However, a check-in drug-likeness for belachinal using Molsoft database (www.molsoft.com/mprop/) suggested that there is only one penalty of Lipin’s key rule of 5 with mol logP 5.78 (> 5). Therefore, the phytoconstituents like belachinal can be chemically modified and approached for studying anti-SARS-CoV-2 properties. In addition, compounds like macaflavanone E and vibsanol B (Fig. 5) have similar binding energy to synthetic drugs that bind to E protein. Moreover, it passes the drug-likeness. However, there was no evidence of its preclinical or clinical studies to determine its effect on SARS-CoV-2, creating a major gap in research. Hence, macaflavanone E and vibsanol B can be further explored for their effect on SARS-CoV-2.

Fig. 5
figure 5

Phytoconstituents inhibiting E protein and their binding energy

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Binding affinity of phytoconstituents with NSP-15 endoribonuclease

Based on the information collected in the literature, a total of 6 phytoconstituents were discovered to bind to the NSP15-endoribonuclease target. According to reports, saikosaponin V, saikosaponin U, saikosaponin K, saikosaponin C, asparoside-D, and asparoside-C all effectively bind to NSP15-endoribonuclease with binding energies of − 8.35 kcal/mol, − 7.27 kcal/mol, − 6.79 kcal/mol, − 6.98 kcal/mol, − 6.44 kcal/mol, and − 7.54 kcal/mol, respectively [35, 38]. Meanwhile, investigations on synthetic drugs with comparable protein targets have been published in the literature, including ceftolozane (− 7.83 kcal/mol), azacitidine (− 6.74 kcal/mol), saquinavir (− 5.76 kcal/mol), and amikacin (− 5.69 kcal/mol) [39]. A drug-likeness assessment utilizing the Molsoft database (www.molsoft.com/mprop/) revealed that saikosaponin V displayed three penalties of Lipin’s main rule of 5 with molecular weight 1106.55 (> 500), number of HBA 24 (> 10), and number of HBD 16 (> 5). Saikosaponin U exhibited three penalties: molecular weight of 1268.60 > 500, a number of HBA of 29 > 10, and a number of HBD of 19 > 5. Similarly, asparoside-D was penalized with three penalties (molecular weight 1198.60 (> 500), number of HBA 27 (> 10), and number of HBD 16 (> 5)) and asparoside-C with molecular weight 1212.61 (> 500), number of HBA 27 (> 10), and number of HBD 15 (> 5) displayed three penalties of Lipin’s fundamental rule of 5. However, because saikosaponin V has higher binding effectiveness than synthetic medicines, it can be chemically manipulated and used to combat SARS-CoV-2.

Binding affinity of phytoconstituents with PL.pro of SARS-CoV-2

According to the current review, asparoside-C was the sole phytoconstituent with a binding energy of − 5.44 kcal/mol with PLpro [35]. Levofloxacin (− 6.8 kcal/mol), dexamethasone (− 6.5 kcal/mol), ciprofloxacin (− 6.1 kcal/mol), and chloroquine (− 5.3 kcal/mol) are some synthetic drugs that bind to the same protein [40]. This essentially implies that phytoconstituents such as asparoside-C might be a viable source of medicines that act on PLpro. However, a check-in drug-likeness for asparoside-C using the Molsoft database (www.molsoft.com/mprop/) suggested that there were three penalties of Lipin’s key rule of 5 with molecular weight 1212.61 (> 500), number of HBA 27 (> 10), and number of HBD 15 (> 5). Although asparoside-C has less binding efficacy than the marketed drugs, it is always wise to further study the anti-SARS-CoV-2 activity with some chemical modification.

Discussion and conclusion

It has been almost a year and a half since the people of the world have been suffering from the infection caused by SARS-CoV-2. It has resulted in an increased incidence of mortality and economic failure. Despite discovering new antiviral drugs, biological products, and potential vaccines to reduce the virus’s activity, people continue to be victims of this deadly virus. Moreover, due to the emergence of new variants that results from rapid mutation change, the virus tends to change its conformation quickly and infect the host more prominently. Based on the increased prevalence of the new COVID-19 variants, scientists have been investigating a plethora of drugs that may be repurposed to fight COVID-19 and many of these drugs are producing severe drug interaction and unwanted side effects. Azithromycin, heparin, and some synthetic drugs like hydroxychloroquine, chloroquine, clozapine, ritonavir, and atazanavir are commonly used to manage COVID-19 severe side effects that affect the hematopoietic system and the cardiovascular system [52]. As discussed earlier, plants and their natural components might have lesser side effects and can potentially reduce the SARS-CoV-2 severity and complexity. In this context, based on the available information reported by various researchers, the current review elaborated on the in silico studies on the inhibiting efficacy of a total of 100 active constituents from plant sources which can be future promising agents to fight against SARS-CoV-2. From the critical findings as represented in Fig. 6, it was observed that the majority of the phytochemical class that effectively binds with the active protein sites of SARS-CoV-2 are flavonoids (20%), coumarins (18%), steroids (18%), and to the lesser extent alkaloids (12%). Interestingly, it was observed that approximately 70% of the active phytochemical constituents (including laurolistine) were shown to bind successfully with the viral for main protease (Mpro) and to a lesser amount with the spike protein and other proteins associated with COVID-19 (Tables 2 and 3). As a result, Mpro might be a possible place for scientists to target medications in order to block or diminish SARS-CoV-2 activity. 7

Fig. 6
figure 6

Diversity of active phytoconstituents binding to SARS-CoV-2 target proteins

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Fig. 7
figure 7

A summary of the phytoconstituents acting on different targets of SARS-CoV-2

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The bioactive phytoconstituents (alkaloids, flavonoids, glucosinolates, phenolics) are repurposed as prospective platforms for anti-SARS-CoV-2 therapies. The present investigations reveal that virtual screening has recently repurposed many phytochemicals such as COVID-19 Mpro. They have mainly bound with the 3-chymotrypsin-like (3CLpro) and papain-like proteases (PLpro), spike glycoprotein, ACE-2, NSP15-endoribonuclease, and E protein targets of SARS-CoV-2 main protease using in silico molecular docking approach. From the current review analysis, it was further observed that different classes of phytoconstituents act at different active sites of the virus (Fig. 7); this includes the following plant metabolites: (a) curcumin, apigenin, quercetin, colchicine, piperine, caffeic acid, chrysophanol, emodin, zingerone, gingerol, and epigallocatechin gallate are significantly binding with spike glycoprotein; (b) laurolistine, acetoside, cryptoquindoline, avicularin, cryptospirolepine, astragalin, and calendoflaside are bound with Mpro; (c) absinthin, 3,5-di-O-galloylshikimic acid, avicularin, cirsimaritin, and hispidulin bind to the ACE-2 target; and (d) macaflavanone E and vibsanol B bind to E protein.

Much of the research gaps were observed from the current review, which may theoretically be regarded as legitimate information for additional exploration by researchers globally. Finally, it is important to identify any key research gaps that resulted from the findings of the current assessment for future perspectives. Such critical gaps include the following: (a) most of the phytoconstituents which were reported in the current review required chemical modification as per the information obtained from drug-likeliness screening; (b) secondly, the data which is reported in the literature solely deals with the virtual screening of phytoconstituents for SARS-CoV-2 inhibition. These research gaps can be critically ascertained and minimized if the studies of the phytoconstituents were done in in vivo models followed by clinical evaluation. In silico data supported in vivo studies; (c) finally, in addition to the 100 phytoconstituents presented in this research, there is a need to delve deeper into new phytoconstituents for probable viral inhibition. This will have a significant influence on encouraging the use of natural items for the treatment of COVID-19-related medical problems.