Efficacy of selected Nigerian tropical plants in the treatment of COVID-19: in silico and in vitro investigations.

The whole world is still challenged with COVID-19 pandemic caused by Coronavirus-2 (SARS-CoV-2) which has affected millions of individuals around the globe. Although there are prophylactic vaccines being used, till now, there is ongoing research into discovery of drug candidates for total eradication of all types of coronaviruses. In this context, this study sought to investigate the inhibitory effects of six selected tropical plants against four pathogenic proteins of Coronavirus-2. The medicinal plants used in this study were selected based on their traditional applications in herbal medicine to treat COVID-19 and related symptoms. The biological activities (antioxidant, free radical scavenging, and anti-inflammatory activities) of the extracts of the plants were assessed using different standard procedures. The phytochemicals present in the extracts were identified using GCMS and further screened via in silico molecular docking. The data from this study demonstrated that the phytochemicals of the selected tropical medicinal plants displayed substantial binding affinity to the binding pockets of the four main pathogenic proteins of Coronavirus-2 indicating them as putative inhibitors of Coronavirus-2 and as potential anti-coronavirus drug candidates. The reaction between these phytocompounds and proteins of Coronavirus-2 could alter the pathophysiology of COVID-19, thus mitigating its pathogenic reactions/activities. In conclusion, phytocompounds of these plants exhibited promising binding efficiency with target proteins of SARS-COV-2. Nevertheless, in vitro and in vivo studies are important to potentiate these findings. Other drug techniques or models are vital to elucidate their compatibility and usage as adjuvants in vaccine development against the highly contagious COVID-19 infection.

Introduction

For several decades, infectious diseases particularly those induced by pathogenic viruses have a significant devastating effect on human wellbeing and health (Oladele et al. 2020a, b, c, d). At present, the whole world is challenged with COVID-19 pandemic caused by Coronavirus-2 (SARS-CoV-2) which has affected millions of individuals around the globe (Huang et al. 2020; Oladele et al. 2021a, b). The SARS-CoV-2 is a betacoronavirus and a member of the Coronaviridae family (Wang et al. 2020). Although there are prophylactic vaccines being used, till now, there is ongoing research into drug candidate for total eradication of all types of coronaviruses and therapy or medication to inhibit the progression of the pathogenesis of the disease. Thus, there is urgent need for the discovery of non-invasive, novel, natural, and non-toxic therapeutic agents that will effectively suppress the pathogenesis of Coronavirus-2.

SARS-CoV-2 belongs to either the alpha or beta human coronaviruses; several processes including pathogenesis, infectivity, virulence, and virus release are mediated by unique structural and accessory proteins (Issa et al 2020; Hassan et al. 2021). Worthy of note are the main protease, primase, ADP ribose phosphatase, replicase protein, and RNA-dependent RNA polymerase (Das et al. 2021; Maio et al. 2021). The activity of the main protease (Mpro), a 33.8 kDa enzyme is highly integral to the release of the viruses’ functional polypeptide via proteolytic processing necessary for its replication and transcription (Zhou et al. 2020), unlike the ADP ribose phosphatase and replicase protein, which are associated with altering the immune response of the host by removal of ADP-ribose from ADP-ribosylated proteins and viral replication (Michalska et al. 2020). Functionally similar to Mpro, the RNA-dependent RNA polymerase has been implicated in the replication of virus genome and gene transcription, making these proteins a potential candidate drug targets in mitigating viral lethality (Maio et al. 2021).

Medicinal plants are used since time immemorial in the treatment of various diseases due to their accessibility, inexpensive natural products, and host broad range of both biologically and chemically active phytocompounds which have been used in the synthesis of therapeutic drugs (Oladele et al. 2020a,b, 2021a, b). They also serve as sources of adjuvants for vaccine development. The six medicinal plants (Neem [Azadirachta indica Juss], Jute [Corchorus olitorius], Cassia alata, Phyllanthus amarus, bitter leaf [Vernonia amygdalina], and Cashew [Anacardium occidentale L.]) used in this study have been reported to have antioxidant, antiviral, immunomodulatory, cytoprotective, and antipyretic properties. Mode of actions of SARS-CoV-2 includes immunosuppression, alteration to physiological functions of alveoli, and activation of c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase (MAPK) pathways leading to secondary hemophagocytic lymphohistiocytosis (sHLH), a cytokine profile with a hyperinflammatory syndrome associated with multiorgan failure linked to COVID-19 severity including lung damage (Oladele et al. 2020c).

Based on the aforementioned, this study sought to investigate the cytoprotective effects of six tropical medicinal plants used in traditional medicine to treat COVID-19-related symptoms and examine the inhibitory ability of the active natural products and phytochemicals present in these plants against five essential proteins implicated in the pathogenesis of COVID-19. Furthermore, the study explores the in vitro biological properties of the plants aqueous extracts.

Materials and methods

Materials

Bovine serum albumin (BSA), folin ciocalteau, Tris–HCl, ethylene diaminetetraacetic acid (EDTA), phenyl methyl sulfonyl fluoride (PMSF), DPPH (1,1-diphenyl-1,2-picrylhydrazyl), TPTZ (2,4,6,-tripyridyl-s-triazine), and deoxyribose were purchased from Sigma Chemical Company, St Louis, Mo, USA. Hydrochloric acid (HCl), methanol, gallic acid, sulphuric acid (H2SO4), sodium carbonate (Na2CO3), aluminium chloride, potassium acetate, potassium persulphate, sodium nitroprusside, hydrogen peroxide, glacial acetic acid, naphthylethylenediamine dichloride, NADH, trichloroacetic acid (TCA), thiobarbituric acid (TBA), and L-ascorbic acid were all purchased from Merck, USA. All other chemicals and reagents used were of analytical grade.

Extraction of the aqueous extracts of the plants

The six tropical medicinal plants (Azadirachta indica Juss, Corchorus olitorius, Cassia alata, Phyllanthus amarus, Vernonia amygdalina, and Anacardium occidentale L.) used in this study are currently used in traditional and herbal medicine to treat and/or prevent COVID-19-related symptoms (Oladele et al. 2020a, b, c, d). Fresh leaves of Azadirachta indica, Corchorus olitorius, Cassia alata, Phyllanthus amarus, Vernonia amygdalina, and bark of Anacardium occidentale were air dried at room temperature in the Biochemistry laboratory of the Department of Chemical Sciences, Faculty of Science, Kings University, Odeomu, Osun State. The dried leaves were pulverized using electric blender. The powdered sample was weighed and soaked in 6 volumes of distilled water for 72 h with constant stirring. The extract was obtained by filtration and the paste was then freeze dried at − 60 °C.

Assessment of biological properties of the aqueous extracts of the plants

Nitric oxide radical scavenging activity

The scavenging effect of aqueous extracts of each plant on nitric oxide radical was measured according to the method of Ebrahimzadeh et al. (2009). Aliquot (1 mL) of sodium nitroprusside (5 mM) in phosphate-buffered saline (PBS, pH 7.2) was mixed with different concentrations of each plant aqueous extracts. This was incubated at room temperature for 150 min after which 0.5 mL of Griess reagent was added. The absorbance of the pink chromophore formed was read at 546 nm. Gallic acid and ascorbic acid were used as positive control. All experiment was done in triplicates. The percentage inhibition was calculated as follows:

Lipid peroxidation inhibition assay

The lipid peroxidation inhibition assay (LPI) was determined according to the method described by Liu et al. (2003) with a slight modification. Excised rat liver was homogenized in phosphate buffer (pH 7.4) and then centrifuged to obtain liposome. Aliquot (0.5 mL) of supernatant, 100 μL 10 mM FeSO4, 100 μL 0.1 mM ascorbic acid, and 0.3 mL of each plant aqueous extracts or standard at different concentrations were mixed to make the final volume of 1 ml. The reaction mixture was incubated at 37 °C for 20 min. Aliquot (1 mL) of (2%) TCA and 1.5 mL of (1%) TBA were added immediately after heating. Finally, the reaction mixture was heated at 100 °C for 15 min and cooled to room temperature. The absorbance was then taken at 532 nm. Percentage inhibition of lipid peroxidation (% LPI) was calculated as follows:where Acontrol is the absorbance of the control and Asample is the absorbance of the extractive/standard. Percentage of inhibition was plotted against concentration.

Ferric reducing power assay

Slightly modified assay method described by Shahi et al. (2020) was employed. Typically, aliquots of the aqueous extracts of each plant were mixed with 0.2 mM phosphate buffer (0.5 mL; pH 6.6) and 0.5 mL potassium ferricyanide (1% w/v). The mixture was incubated at 50 °C for 20 min. Trichloroacetic acid (10%, 2.5 mL) was added to the mixture and centrifuged at 2500 rpm for 10 min. Aliquot (1 mL) of obtained supernatant was mixed with 1 mL FeCl (0.1%, 0.5 mL), and the absorbance was measured at 700 nm. Gallic acid and ascorbic acid were used as positive standard.

Hydroxyl radical scavenging activity

The hydroxyl radical scavenging activity of aqueous extracts of each plant was carried out using the assay method of Kim and Minamikawa (1997) as described by Shahi et al. (2020) with slight modifications. Briefly, 0.1 mL of 10 mM EDTA, 0.01 mL of 10 mM FeCl3, 0.1 mL of 10 mM H2O2, 0.36 mL of 10 mM deoxyribose, 1.0 mL of aqueous extracts of each plant, 0.33 mL of phosphate buffer (50 mM, pH 7.4), and 0.1 mL of ascorbic acid were added sequentially. Resulting mixture was then incubated at 37 °C for 1 h. Aliquot (1.0 mL) of 5% TCA and 1.0 mL of 0.5% TBA were added to develop the pink chromogen measured at 532 nm. The standard was gallic acid and ascorbic acid. The percentage of hydroxyl radical scavenged was estimated using the following equation:where Acontrol is the absorbance of control and Asample is the absorbance of sample solution.

DPPH radical scavenging assay

Assay method of Wu et al. (2003) with slight modifications was employed. Briefly, aliquots (1 mL) of varying concentrations (50–800 mg/mL) of aqueous extracts of each plant were added to 1 mM 2, 2 diphenyl-1-picryldydrazyl (DPPH) (1 mL) in methanol solution. Resulting mixtures were vortexed, centrifuged (2500 rpm for 10 min), and then incubated in a dark chamber for 30 min at room temperature. Absorbance of the supernatant was measured at 517 nm against DPPH control containing 1 mL methanol in place of the protein fractions. Gallic acid and ascorbic acid were used as positive standard. Inhibition of DPPH radical was calculated as a percentage using the expression:where Ablank was standard absorbance and Asample was sample absorbance.

Scavenging of hydrogen peroxide

The ability of the aqueous extracts of each plant to scavenge hydrogen peroxide was determined according to Nabavi et al. (2008) and (2009). A solution of hydrogen peroxide (40 mM) was prepared in phosphate buffer (pH 7.4). The concentration of hydrogen peroxide was determined by absorption at 230 nm using a spectrophotometer. Aqueous extracts of each plant (50–800 mg/ ml) in distilled water were added to a hydrogen peroxide solution (0.6 mL, 40 mM). The absorbance of hydrogen peroxide at 230 nm was determined after 10 min against a blank solution containing phosphate buffer without hydrogen peroxide. The percentage of hydrogen peroxide scavenging by the aqueous extracts of each plant and a standard compound was calculated as follows:where Ao was the absorbance of the control and A1 was the absorbance in the presence of the sample of aqueous extracts of each plant and standard.

Gas chromatography-mass spectroscopy (GC–MS) analysis of the extract

The GC–MS analysis was carried out to determine the phytochemicals present in the aqueous extracts using GC–MS (Model: QP2010 plus Shimadzu, Japan) encompassing an AOC-20i auto-sampler and gas chromatograph interfaced to a mass spectrometer (GC–MS). The relative percentage of the analyte was expressed as a percentage with peak area normalization. Interpretation on the mass spectrum was conducted using the database of National Institute of Standards and Technology (NIST). The fragmentation pattern spectra of the unknown components were compared with those of known components stored in the NIST library (NIST 11). The relative percentage of each phytochemical was calculated by comparing its average peak area to the total area. The name, molecular weight, and structure of the components of the test materials were ascertained.

In silico studies

Protein preparation

The crystal structures of SARS coronavirus spike receptor-binding domain (PDB ID 2AJF) with resolution 2.90 Å, ADP ribose phosphatase of NSP3 from SARS CoV-2 (PDB ID 6VXS) with resolution 2.03 Å, SARS-COV2 major protease (PDB ID 6LU7) with resolution 2.16 Å, and SARS CoV-2 RNA-dependent RNA polymerase (PDB ID 7BTF) with resolution 2.95 Å were retrieved from the protein databank (www.rcsb.org). Before the docking and analysis, the crystal structures were processed by eliminating existing ligands and water molecules. Furthermore, missing hydrogen atoms were added using Autodock v4.2 program, Scripps Research Institute (Morris et al. 2009). Subsequently, non-polar hydrogens were merged while polar hydrogen was added and then saved into pdbqt format in preparation for molecular docking.

Ligand preparation

The SDF structures of phytochemical present in the extracts as identified by GC–MS were retrieved from the PubChem database (www.pubchem.ncbi.nlm.nih.gov). The phytochemicals were converted to mol2 chemical format. Polar hydrogens were added while non-polar hydrogens were merged with the carbons, and the internal degrees of freedom and torsions were set. The protein and ligand molecules were further converted to the dockable PDBQT format using Autodock tools.

Molecular docking

Docking of the phytochemicals to the targeted protein and determination of binding affinities was carried out using AutodockVina (Trott and Olson 2010). The PDBQT formats of the receptor and that of the phytochemicals were positioned at their respective columns, and the software was run. The binding affinities of phytochemicals for the protein target were recorded. The phytochemicals were then ranked by their affinity scores. The molecular interactions between the receptor and phytochemicals with most remarkable binding affinities were viewed with PYMOL.

ADMET analysis

The solubility, pharmacodynamics, pharmacokinetics, and toxicological profiles of phytochemicals with the best docking score were computed based on their ADMET (absorption, distribution, metabolism, elimination, and toxicity) studies using pkCSM tool (http://biosig.unimelb.edu.au/pkcsm/prediction). The canonical SMILE molecular structures of the compounds used in the studies were obtained from PubChem (pubchem.ncbi.nlm.nih.gov).

Results

Biological properties of the aqueous extracts of the plants

Nitric oxide inhibitory activity of the aqueous extracts of the plants

Figure 1 shows a significant increase in the nitric oxide inhibitory activity of all aqueous extracts of the selected medicinal plants at various concentrations used in this study. At 800 mg/ml, ALVA (aqueous leaf extract of Vernonia amygdalina) displayed the highest nitric oxide inhibitory activity among the six plant extracts. Also, ALVA exhibited higher activity than ascorbic acid but not up to activity of the gallic acid. This confirms the possible anti-inflammatory potential of the aqueous extracts.

Fig. 1

Nitric oxide inhibitory activity of aqueous extracts of selected medicinal plants. ALAI, aqueous leaf extract of Azadirachta indica; ALAO, aqueous leaf extract of Corchorus olitorius; ALCA, aqueous leaf extract of Cassia alata; ALPA, aqueous leaf extract of Phyllanthus amarus; ALVA, aqueous leaf extract of Vernonia amygdalina; ABAO, aqueous bark extract of Anacardium occidentale

Lipid peroxidation inhibitory activity of the aqueous extracts of the plants

The result in Fig. 2 revealed that the aqueous extracts of the selected plants demonstrated increased lipid peroxidation inhibitory activity with increase in the concentration of the extracts. However, at 800 mg/ml, ABAO (aqueous bark extract of Anacardium occidentale) exhibited highest lipid peroxidation inhibitory activity when compared with other extracts. Similarly, ABAO displayed higher inhibitory activity than ascorbic acid when compared with the standard antioxidants used. In all, gallic acid has the highest activity. This study revealed that the extracts could mitigate the lipid peroxidation chain reactions and prevent oxidation of cellular macromolecules.

Fig. 2

Lipid peroxidation inhibitory activity of aqueous extracts of selected medicinal plants. ALAI, aqueous leaf extract of Azadirachta indica; ALAO, aqueous leaf extract of Corchorus olitorius; ALCA, aqueous leaf extract of Cassia alata; ALPA, aqueous leaf extract of Phyllanthus amarus; ALVA, aqueous leaf extract of Vernonia amygdalina; ABAO, aqueous bark extract of Anacardium occidentale

Ferric reducing power of the aqueous extracts of the plants

The result in Fig. 3 revealed the ferric reducing power of different concentrations of the aqueous extracts of the selected plants compared with standard antioxidants (ascorbic and tannic acids). At 800 mg/ml, all the extracts expect ALAO (aqueous leaf extract of Corchorus olitorius) displayed higher ferric radical reducing power than ascorbic acid when compared with standard antioxidants used. Of note, ABAO exhibited the highest ferric reducing power activity at 800 mg/mL among all the plant extracts used in the study.

Fig. 3

Free radical reducing power of aqueous extracts of selected medicinal plants. ALAI, aqueous leaf extract of Azadirachta indica; ALAO, aqueous leaf extract of Corchorus olitorius; ALCA, aqueous leaf extract of Cassia alata; ALPA, aqueous leaf extract of Phyllanthus amarus; ALVA, aqueous leaf extract of Vernonia amygdalina; ABAO, aqueous bark extract of Anacardium occidentale

Hydroxyl radical scavenging ability of the aqueous extracts of the plants

Results in Fig. 4 showed that at 800 mg/ml, ALAI (aqueous leaf extract of Azadirachta indica), ALCA (aqueous leaf extract of Cassia alata), ALVA (aqueous leaf extract of Vernonia amygdalina), and ABAO (aqueous bark extract of Anacardium occidentale) have higher potent hydroxyl radical scavenging ability than ascorbic acid when compared with the standard antioxidants used. At all the tested concentrations, all the aqueous plant extracts displayed high hydroxyl radical scavenging ability with increase in their concentrations suggesting the extracts as potent source of antioxidant phytochemicals.

Fig. 4

Hydroxyl radical scavenging activity of aqueous extracts of selected medicinal plants. ALAI, aqueous leaf extract of Azadirachta indica; ALAO, aqueous leaf extract of Corchorus olitorius; ALCA, aqueous leaf extract of Cassia alata; ALPA, aqueous leaf extract of Phyllanthus amarus; ALVA, aqueous leaf extract of Vernonia amygdalina; ABAO, aqueous bark extract of Anacardium occidentale

DPPH inhibitory activity of the aqueous extracts of the plants

The result in Fig. 5 shows that all the aqueous extracts of the selected medicinal plants used in this study elicited impressive DPPH radical scavenging activities when compared with standard antioxidants: gallic acid and ascorbic acid. At 800 mg/ml, ALVA (aqueous leaf extract of Vernonia amygdalina) exhibited the highest DPPH scavenging activity among all the extract used, followed by ABAO (aqueous bark extract of Anacardium occidentale) and then ALCA (aqueous leaf extract of Cassia alata) and ALPA. Although none of the extracts exhibited higher DPPH radical scavenging activity than the antioxidant standards used, their activity is significant, and this result depicted that they have substantial DPPH radical scavenging activity as the standard antioxidants.

Fig. 5

DPPH radical scavenging activity of aqueous extracts of selected medicinal plants. ALAI, aqueous leaf extract of Azadirachta indica; ALAO, aqueous leaf extract of Corchorus olitorius; ALCA, aqueous leaf extract of Cassia alata; ALPA, aqueous leaf extract of Phyllanthus amarus; ALVA, aqueous leaf extract of Vernonia amygdalina; ABAO, aqueous bark extract of Anacardium occidentale

Hydrogen peroxide inhibitory activity of the aqueous extracts of the plants

Hydrogen peroxide scavenging activity of all the aqueous extracts of the plants used in this study was presented in Fig. 6 as compared with the standard antioxidants (ascorbic and gallic acids). At tested concentrations, all the aqueous extracts efficiently scavenged hydrogen peroxide. Interestingly, at 800 mg/ml, ALAI exhibited the highest hydrogen peroxide scavenging activity when compared with the standard antioxidants used and other extracts. Similarly, all the extracts expect ALVA displayed higher hydrogen peroxide scavenging activity than ascorbic acid. This result indicated that all the extracts could play beneficial role in mitigating pathological conditions mediated by oxidative stress.

Fig. 6

Hydrogen peroxide scavenging activity of aqueous extracts of selected medicinal plants. ALAI, aqueous leaf extract of Azadirachta indica; ALAO, aqueous leaf extract of Corchorus olitorius; ALCA, aqueous leaf extract of Cassia alata; ALPA, aqueous leaf extract of Phyllanthus amarus; ALVA, aqueous leaf extract of Vernonia amygdalina; ABAO, aqueous bark extract of Anacardium occidentale

Phytochemical constituents and GCMS analysis of the extract

The preliminary qualitative phytochemical screening of extracts of the selected tropical plants used in this study revealed that the extracts are rich in phenol, flavonoids, coumarins, saponin, and alkaloids. The secondary metabolites profile of each of the extracts was detailed in Tables 1, 2, 3, 4, 5 and 6 as analysed using NIST 11 (Figs. 7, 8, 9, 10, 11 and 12). Some of the identified phytochemicals in the extracts have been reported to have antiapoptotic, antioxidant, anti-inflammatory, and cytoprotective effects which are essential to mitigate inflammation, oxidative stress, and toxicity effects mediated by Coronavirus-2.

Table 1

GC–MS analysis of aqueous leaf of Azadirachta indica

S/N	Compound	Canonical SMILES	PubChem CID
1	Ethyl acetate	CCOC(= O)C	8857
2	2-Propenal	C = CC = O	7847
	2-Propen-1-amine	C = CCN	7853
3	Acetic acid, butyl ester	CCCCOC(= O)C	31,272
4	3-Hexanone, 2-methyl-	CCCC(= O)C(C)C	23,847
	3,4-Dimethylpent-2-en-1-ol	CC(C)C(= CCO)C	5,366,252
	1,1-Di(isobutyl)acetone	CC(C)CC(CC(C)C)C(= O)C	551,338
5	Ethylbenzene	CCC1 = CC = CC = C1	7500
	o-Xylene	CC1 = CC = CC = C1C	7237
6	n-Butyl ether	CCCCOCCCC	8909
	Propanoic acid, 2-methylpropyl ester	CCC(= O)OCC(C)C	10,895
	n-Butyl ether	CCCCOCCCC	8909
7	Ethane, 1-chloro-2-isocyanato-	C(CCl)N = C = O	16,035
	1-[N-Aziridyl]heptene-3	CCCC = CCCN1CC1	5,364,877
	1-Heptene, 2-methyl-	CCCCCC(= C)C	27,519
8	1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane	CC1(CC(C2 = C1C = CC(= C2)OC)(C)C3 = CC = C(C = C3)OC)C	624,568
	1-[2,4-Bis(trimethylsiloxy)phenyl] -2-[(4-trimethylsiloxy)phenyl]prop an-1-one
	Chloromethyl octyl ether	CCCCCCCCOCCl	534,743
9	Cyclohexane, 1R-acetamido-2,3-cis-epoxy-4-cis-formyloxy-	CC(= O)NC1CCC(C2C1O2)OC = O	537,204
	Chloroacetic acid, 2-methylpentylester
	Cyclohexanol, 1R-4-acetamido-2,3-cis-epoxy-	CC(= O)NC1CCC(C2C1O2)OC = O	537,204
10	Butane, 2,2′-thiobis-	C(CCO)CO.C(CSCCO)O	44,153,764
	1,6-Anhydro-2,3-dideoxy-.beta.-D-erythro-hexopyranose	C1CC2OCC(C1O)O2	560,102
	Boronic acid, ethyl-, bis(2-mercaptoethyl ester)	C1CC2OCC(C1O)O2	560,102
11	Silanol, trimethyl-, propanoate	CCC(= O)O[Si](C)(C)C	519,321
	.beta.-D-Ribopyranoside, methyl 2, 3,4-tri-O-methyl-	COC1COC(C(C1OC)OC)OC	21,140,439
	Hexadecanoic acid, 3,7,11,15-tetramethyl-, methyl ester	CC(C)CCCC(C)CCCC(C)CCCC(C)CC(= O)OC	568,163
12	N1,N1-Dimethyl-N2-(1-phenyl–ethyl) -ethane-1,2-diamine	CC(C1 = CC = CC = C1)NCCN(C)C	547,403
	2-Nonanone	CCCCCCCC(= O)C	13,187
13	4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester	CCOC(= O)C1 = C(C(= C(N1)C)C2C(= C(OC3 = C2C(= O)CCC3)N)C#N)C	605,143
	Heptasiloxane, 1,1,3,3,5,5,7,7,9,9,11,11,13,13-tetradecamethyl-	C[Si](C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)C	6,329,088
	1H-Indole-2-carboxylic acid, 6-(4-ethoxyphenyl)-3-methyl-4-oxo-4,5,6 ,7-tetrahydro-, isopropyl ester	CCOC1 = CC = C(C = C1)C2CC3 = C(C(= C(N3)C(= O)OC(C)C)C)C(= O)C2	4,916,205
14	Octasiloxane, 1,1,3,3,5,5,7,7,9,9, 11,11,13,13,15,15-hexadecamethyl-	C[Si](C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)C	6,329,087
	Heptasiloxane, 1,1,3,3,5,5,7,7,9,9,11,11,13,13-tetradecamethyl-	C[Si](C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)C	6,329,088
	Furo[2′,3′:4,5]thiazolo[3,2-g]purine-8-methanol, 4-amino-6.alpha.,7, 8,9a-tetrahydro-7-hydroxy-, [6aS-( 6a.alpha.,7.alpha.,8.beta.,9a.alph a.)]-
15	Dodecanoic acid	CCCCCCCCCCCC(= O)O	3893
	Methyl 6-O-[1-methylpropyl]-.beta. -d-galactopyranoside	CCC(C)OCC1C(C(C(C(O1)OC)O)O)O	22,213,632
	Nonanoic acid	CCCCCCCCC(= O)O	8158
16	n-Decanoic acid	CCCCCCCCCC(= O)O	2969
	Trisilane	C[Si](C)(C)[Si](C)(C)[Si](C)(C)C1 = CC = CC2 = CC = CC = C21	142,270
	4a-Methyl-6,8-dioxa-3-thia-bicyclo(3,2,1)octane		50,469,286
17	Butane, 1,1-dibutoxy-	CCCCOC(CCC)OCCCC	22,210
	1,1-Diisobutoxy-isobutane	CC(C)COC(C(C)C)OCC(C)C	545,267
	1-Butoxy-1-isobutoxy-butane	CCCCOC(CCC)OCC(C)C	545,190
18	Undec-10-ynoic acid	C#CCCCCCCCCC(= O)O	31,039
19	1-Pentadecyne	CCCCCCCCCCCCCC#C	69,825
20	Spirohexan-4-one, 5,5-dimethyl-	CC1(CC2(C1 = O)CC2)C	534,214
	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	Cyclohexanone, 2-(2-propenyl)-	C = CCC1CCCCC1 = O	78,944
21	Spirohexan-4-one, 5,5-dimethyl-	CC1(CC2(C1 = O)CC2)C	534,214
	1-Methoxymethoxy-oct-2-yne	CCCCCC#CCOCOC	542,329
	Thioctic acid	C1CSSC1CCCCC(= O)O	864
22	9,12-Octadecadienoic acid (Z,Z)-	CCCCCC = CCC = CCCCCCCCC(= O)O	5,280,450
23	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
24	Chloroacetic acid, 1-cyclopentylet hyl ester	CC(C1CCCC1)OC(= O)CCl	543,343
25	(4-Methoxymethoxy-hex-5-ynylidene) -cyclohexane	COCOC(CCC = C1CCCCC1)C#C	542,331
26	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
	3-Hydroxy-3-trifluoromethyl-2-oxa-spiro[5.5]undecan-5-one	C1CCC2(CC1)COC(CC2 = O)(C(F)(F)F)O	557,008
27	Cyclohexanol, 2-(2-propynyloxy)-, trans-	C#CCOC1CCCCC1O	12,522,342
	5-Methoxymethoxyhexa-2,3-diene	CC = C = CC(C)OCOC	542,425
	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
28	Spirohexan-4-one, 5,5-dimethyl-	CC1(CC2(C1 = O)CC2)C	534,214
	3-Hydroxy-3-trifluoromethyl-2-oxa- spiro[5.5]undecan-5-one	C1CCC2(CC1)COC(CC2 = O)(C(F)(F)F)O	557,008
	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
29	9,12-Octadecadienoic acid (Z,Z)-	CCCCCC = CCC = CCCCCCCCC(= O)O	5,280,450
30	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	1-Methoxymethoxy-oct-2-yne	CCCCCC#CCOCOC	542,329
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
31	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	Spirohexan-4-one, 5,5-dimethyl-	CC1(CC2(C1 = O)CC2)C	534,214
	Cyclopentaneethanol, 2 (hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
32	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	3-Hydroxy-3-trifluoromethyl-2-oxa- spiro[5.5]undecan-5-one	C1CCC2(CC1)COC(CC2 = O)(C(F)(F)F)O	557,008
	Chloroacetic acid, 1-cyclopentylethyl ester	CC(C1CCCC1)OC(= O)CCl	543,343
33	Spirohexan-4-one, 5,5-dimethyl-	CC1(CC2(C1 = O)CC2)C	534,214
	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
34	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	3H-Naphth[1,8a-b]oxiren-2(1aH)-one, hexahydro-	C1CCC23C(C1)CCC(= O)C2O3	548,904
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138

Table 2

GC–MS analysis of aqueous leaf of Corchorus olitorius

S/N	Compound	Canonical SMILES	PubChem CID
1	Ethyl acetate	CCOC(= O)C	8857
	Acetic acid, pentyl ester	CCCCCOC(= O)C	12,348
2	2-Propenal	C = CC = O	7847
	2-Propen-1-amine	C = CCN	7853
3	2-Propenal	C = CC = O	7847
	2-Propen-1-amine	C = CCN	7853
4	Acetic acid, butyl ester	CCCCOC(= O)C	31,272
5	3-Hexanone, 2-methyl-	CCCC(= O)C(C)C	23,847
	Butyric acid, 2,2-dimethyl-, vinyl ester	CCC(C)(C)C(= O)OC = C	537,729
6	o-Xylene	CC1 = CC = CC = C1C	7237
	Benzene, 1,3-dimethyl-	CC1 = CC(= CC = C1)C	7929
7	n-Butyl ether	CCCCOCCCC	8909
	Formic acid, 3,3-dimethylbut-2-yl ester	CC(C(C)(C)C)OC = O	54,488,145
8	4-Ethyl-4-methyl-5-methylene-[1,3] dioxolan-2-one	CCC1(C(= C)OC(= O)O1)C	544,710
	1,1-Cyclohexanedicarbonitrile	C1CCC(CC1)(C#N)C#N	544,561
	Ethane, 1-chloro-2-isocyanato-	C(CCl)N = C = O	16,035
9	Acetamide, N-cyclohexyl-	CC(= O)NC1CCCCC1	14,301
	Acetamide, N-(4-hydroxycyclohexyl) -, cis-	CC(= O)NC1CCC(CC1)O	90,074
	L-Lyxose	C(C(C(C(C = O)O)O)O)O	644,176
10	12,12-Dimethoxydodecanoic acid, methyl ester	COC(CCCCCCCCCCC(= O)OC)OC	554,421
	Hexadecane, 1,1-dimethoxy-	CCCCCCCCCCCCCCCC(OC)OC	76,037
	1-Propene, 3,3-dichloro-	C = CC(Cl)Cl	11,244
11	Isopropyl isothiocyanate	CC(C)N = C = S	75,263
	Tridecyl (E)-2-methylbut-2-enoate	CCCCCCCCCCCCCOC(= O)C(= CC)C	91,701,893
	3-Phenylpropionic acid, 4-methoxy- 2-methylbutyl ester	CC(CCOC)COC(= O)CCC1 = CC = CC = C1	91,702,047
12	Hexasiloxane, 11,11-dodecamethyl-	C[Si](C)(O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)Cl)O[Si](C)(C)O[Si](C)(C)Cl	553,580
	Octasiloxane, 1,1,3,3,5,5,7,7,9,9, 11,11,13,13,15,15 hexadecamethyl-	C[Si](C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)C	6,329,087
	9-Bromononanoic acid	C(CCCCBr)CCCC(= O)O	548,221
13	Hexasiloxane, tetradecamethyl-	C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C	7875
	Octasiloxane, 1,1,3,3,5,5,7,7,9,9, 11,11,13,13,15,15-hexadecamethyl-	C[Si](C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)C	6,329,087
	1-Butyl-3,4-dihydroxy-	CCCCCNC(= O)C1C(C(CN1CCCC)O)O	6,420,934
	pyrrolidine- 2,5-dione	C1C(C(= O)N(C1 = O)C2 = CC = C(C = C2)F)SCCN	2,756,427
14	11-Bromoundecanoic acid	C(CCCCCBr)CCCCC(= O)O	17,812
	2-Ethylacridine	CCC1 = CC2 = CC3 = CC = CC = C3N = C2C = C1	610,161
	N-Cyclododecylacetamide	CC(= O)NC1CCCCCCCCCCC1	548,224
15	Octadecanoic acid	CCCCCCCCCCCCCCCCCC(= O)O	5281
	Polygalitol	C1C(C(C(C(O1)CO)O)O)O	64,960
	Acetamide, N-cyclohexyl-2-[(2-furanylmethyl)thio]-	C1CCC(CC1)NC(= O)CSCC2 = CC = CO2	5,298,618
16	Butane, 1,1-dibutoxy-	CCCCOC(CCC)OCCCC	22,210
	1-Butoxy-1-isobutoxy-butane	CCCCOC(CCC)OCC(C)C	545,190
	1,1-Diisobutoxy-isobutane	CC(C)COC(C(C)C)OCC(C)C	545,267
17	1-Butyl-3,4-dihydroxy-pyrrolidine- 2,5-dione	CCCCN1C(= O)C(C(C1 = O)O)O	6,420,934
	L-Galactose, 6-deoxy-	CC(C(C(C(C = O)O)O)O)O	3,034,656
	Nonanoic acid	CCCCCCCCC(= O)O	8158
18	9,12-Octadecadienoic acid (Z,Z)-	CCCCCC = CCC = CCCCCCCCC(= O)O	5,280,450
	9-Octadecyne	CCCCCCCCC#CCCCCCCCC	141,998
	Undec-10-ynoic acid	C#CCCCCCCCCC(= O)O	31,039
19	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	3H-Naphth[1,8a-b]oxiren-2(1aH)-one, hexahydro-	C1CCC23C(C1)CCC(= O)C2O3	548,904
	Cyclohexanone, 2-(2-propenyl)-	C = CCC1CCCCC1 = O	78,944
20	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	Thioctic acid	C1CSSC1CCCCC(= O)O	864
	3H-Naphth[1,8a-b]oxiren-2(1aH)-one, hexahydro-	C1CCC23C(C1)CCC(= O)C2O3	548,904
21	Spirohexan-4-one, 5,5-dimethyl-	CC1(CC2(C1 = O)CC2)C	534,214
	1-Methoxymethoxy-oct-2-yne	CCCCCC#CCOCOC	542,329
	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
22	Thioctic acid	C1CSSC1CCCCC(= O)O	864
	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	(4-Methoxymethoxy-hex-5-ynylidene -cyclohexane	COCOC(CCC = C1CCCCC1)C#C	542,331
23	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	1-Naphthalenemethanol, decahydro-5 -(5-hydroxy-3-methyl-3-pentenyl)-1 ,4a-dimethyl-6-methylene-, [1S-[1.alpha.,4a.alpha.,5.alpha.(E),8a.beta.]]-	CC(= CCO)CCC1C(= C)CCC2C1(CCCC2(C)CO)C	5,316,778
	3-Hydroxy-3-trifluoromethyl-2-oxa spiro[5.5]undecan-5-one	C1CCC2(CC1)COC(CC2 = O)(C(F)(F)F)O	557,008
24	1-Naphthalenemethanol, decahydro-5 -(5-hydroxy-3-methyl-3-pentenyl)-1 ,4a-dimethyl-6-methylene-, [1S-[1.alpha.,4a.alpha.,5.alpha.(E),8a.be ta.]]-	CC(= CCO)CCC1C(= C)CCC2C1(CCCC2(C)CO)C	5,316,778
	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	3H-Naphth[1,8a-b]oxiren-2(1aH)-one, hexahydro-	C1CCC23C(C1)CCC(= O)C2O3	548,904
25	Cyclobutanone, 2-methyl-2-oxiranyl	CC1(CCC1 = O)C2CO2	534,052
	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
26	Borolane, 3-ethyl-4-methyl-1,2,2-tris(1-methylethyl)-	B1(CC(C(C1(C(C)C)C(C)C)CC)C)C(C)C	535,085
	3H-Naphth[1,8a-b]oxiren-2(1aH)-one, hexahydro-	C1CCC23C(C1)CCC(= O)C2O3	548,904
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
27	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
	Cyclohexanol, 2-(2-propynyloxy)-, trans-	C#CCOC1CCCCC1O	12,522,342
	Spiro[2.3]hexan-4-one, 5,5-diethyl	CCC1(CC2(C1 = O)CC2)CC	534,343
28	3- Oxatricyclo[4.2.0.0(2,4)]octan -one	C1C2C(CC2 = O)C3C1O3	556,833
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
	Cyclododecanol, 1-aminomethyl-	C1CCCCCC(CCCCC1)(CN)O	533,851
29	Cyclobutanone, 2-methyl-2-oxiranyl	CC1(CCC1 = O)C2CO2	534,052
	Spiro[2.3]hexan-4-one, 5,5-diethyl	CCC1(CC2(C1 = O)CC2)CC	534,343
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
30	Cyclohexanol, 2-(2-propynyloxy)-, trans-	C#CCOC1CCCCC1O	12,522,342
	8-Azabicyclo[3.2.1]octane-2-carboxylic acid, 3-hydroxy-8-methyl-, (2-endo,3-exo)-	CN1C2CC1C(C(C(C2)O)C(= O)[O-])O	54,613,783
	Cyclobutanone, 2-methyl-2-oxiranyl	CC1(CCC1 = O)C2CO2	534,052
31	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	Spirohexan-4-one, 5,5-dimethyl-	CCC1(CC2(C1 = O)CC2)CC	534,343
	5-Methoxymethoxyhexa-2,3-diene	CC = C = CC(C)OCOC	542,425
32	Spirohexan-4-one, 5,5-dimethyl-	CCC1(CC2(C1 = O)CC2)CC	534,343
	Cyclopentaneethanol, 2-(hydroxyl methyl)-.beta.,3-dimethyl-
	5-Methoxymethoxyhexa-2,3-diene	CC = C = CC(C)OCOC	542,425
33	Borolane, 3-ethyl-4-methyl-1,2,2-tris(1-methylethyl)-	B1(CC(C(C1(C(C)C)C(C)C)CC)C)C(C)C	535,085
	3H-Naphth[1,8a-b]oxiren-2(1aH)-one, hexahydro-	C1CCC23C(C1)CCC(= O)C2O3	548,904
	Thioctic acid	C1CSSC1CCCCC(= O)O	864
34	5-Methoxymethoxyhexa-2,3-diene	CC = C = CC(C)OCOC	542,425
	Cyclohexanol, 2-(2-propynyloxy)-, trans-	C#CCOC1CCCCC1O	12,522,342
	Ethane, 1,2-dichloro-1,1,2-trifluoro-	C(C(F)(F)Cl)(F)Cl	9631
35	5-Methoxymethoxyhexa-2,3-diene	CC = C = CC(C)OCOC	542,425
	Cyclohexanone, 2-(2 propenyl)-	CC(= CC1CCCCC1 = O)C	592,361
	3-Hydroxy-3-trifluoromethyl-2-oxa-spiro[5.5]undecan-5-one	C1CCC2(CC1)COC(CC2 = O)(C(F)(F)F)O	557,008
36	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	Spirohexan-4-one, 5,5-dimethyl-	CCC1(CC2(C1 = O)CC2)CC	534,343
	3H-Naphth[1,8a-b]oxiren-2(1aH)-one, hexahydro-	C1CCC23C(C1)CCC(= O)C2O3	548,904

Table 3

GC–MS analysis of aqueous leaf of Cassia alata

S/N	Compound	Canonical SMILES	PubChem CID
1	Acetic acid, butyl ester	CCCCOC(= O)C	31,272
2	3-Hexanone, 2-methyl-	CCCC(= O)C(C)C	23,847
	Acetaldehyde, butylhydrazone	CCCCNN = CC	9,601,789
	Butyric acid, 2,2-dimethyl-, vinyl ester	CCC(C)(C)C(= O)OC = C	537,729
3	o-Xylene	CC1 = CC = CC = C1C	7237
	1-Oxa-4-azaspiro[4.5]decan-4-oxyl, 3,3-dimethyl-8-oxo-	CC1(COC2([N +]1 = O)CCC(= O)CC2)C	6,420,654
	1,3,2-Dioxaborinane, 2-ethyl-5,5-dimethyl-	B1(OCC(CO1)(C)C)CC	544,611
4	n-Butyl ether	CCCCOCCCC	8909
	Propanoic acid, 2-methylpropyl ester	CCC(= O)OCC(C)C	10,895
5	Pyrazol-3(2H)-one, 4-(2-furfurylidenamino)-1,5-dimethyl-2-phenyl-	CC1 = C(C(= O)N(N1C)C2 = CC = CC = C2)N = CC3 = CC = CO3	624,533
	Cyclohexaneacetic acid, butyl este	CCCCOC(= O)CC1CCCCC1	251,210
	Furo[2′,3′:4,5]thiazolo[3,2-g]purine-8-methanol, 4-amino-6.alpha.,7,8,9a-tetrahydro-7-hydroxy-, [6aS-(6a.alpha.,7.alpha.,8.beta.,9a.alph a.)]-
6	6-Azaestra-1,3,5(10),6,8-pentaen-1,7-one, 3-methoxy-
	Pyrazol-3(2H)-one, 4-(2-furfurylidenamino)-1,5-dimethyl-2-phenyl-	CC1 = C(C(= O)N(N1C)C2 = CC = CC = C2)N = CC3 = CC = CO3	624,533
	1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane	CC1(CC(C2 = C1C = CC(= C2)OC)(C)C3 = CC = C(C = C3)OC)C	624,568
7	Cyclohexane, 1R-acetamido-2,3-cis-epoxy-4-cis-formyloxy-	CC(= O)NC1CCC(C2C1O2)OC = O	537,204
	Cyclohexaneacetic acid, butyl este	CCCCOC(= O)CC1CCCCC1	251,210
	Cyclopentaneundecanoic acid	C1CCC(C1)CCCCCCCCCCC(= O)O	534,549
8	Hexyl 2-hydroxyethyl sulfide	CCCCCCSCCO	90,519
	D-Arabinitol	C(C(C(C(CO)O)O)O)O	94,154
	Ribitol	C(C(C(C(CO)O)O)O)O	6912
9	Silanol, trimethyl-, propanoate	CCC(= O)O[Si](C)(C)C	519,321
	6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsu lfanyl-ethyl ester
	2-Octanol, 8,8-dimethoxy-2,6-dimethyl-	CC(CCCC(C)(C)O)CC(OC)OC	31,272
10	Ethanol, 2-phenoxy-, propanoate	CCC(= O)OCCOC1 = CC = CC = C1	31,954
	Tridecyl (E)-2-methylbut-2-enoate	CCCCCCCCCCCCCOC(= O)C(= CC)C	91,701,893
11	Butane, 1,1-dibutoxy-	CCCCOC(CCC)OCCCC	22,210
	1-Butoxy-1-isobutoxy-butane	CCCCOC(CCC)OCC(C)C	545,190

Table 4

GC–MS analysis of aqueous leaf of Phyllanthus amarus

S/N	Compound	Canonical SMILES	PubChem CID
1	Acetic acid, butyl ester	CCCCOC(= O)C	31,272
2	3-Hexanone, 2-methyl-	CCCC(= O)C(C)C	23,847
	Butyric acid, 2,2-dimethyl-, vinylester	CCC(C)(C)C(= O)OC = C	537,729
	2-Methylvaleroyl chloride	CCCC(C)C(= O)Cl	107,385
3	o-Xylene	CC1 = CC = CC = C1C	7237
	1-Hexene, 3,4-dimethyl-	CCC(C)C(C)C = C	140,134
	2H-Pyran-2-one, tetrahydro-5,6-dimethyl-, trans-	CC1CCC(= O)OC1C	11,029,861
4	n-Butyl ether	CCCCOCCCC	8909
	Formic acid, 3,3-dimethylbut-2-ylester	CC(C(C)(C)C)OC = O	54,488,145
5	Pentane, 1-bromo-3,4-dimethyl-	CC(C)C(C)CCBr	544,665
	Butanoic acid, butyl ester	CCCCOC(= O)CCC	7983
	Cyclododecylamine	C1CCCCCC(CCCCC1)N	2897
6	Pentane, 1-bromo-3,4-dimethyl-	CC(C)C(C)CCBr	544,665
	Pentane, 2,3-dimethyl-	CCC(C)C(C)C	11,260
	2,4-Dipropyl-5-ethyl-1,3-dioxane	CCCC1C(COC(O1)CCC)CC	221,917
7	n-Butyl isobutyl sulfide	CCCCSCC(C)C	525,418
	1,6-Anhydro-2,3-dideoxy-.beta.-D-erythro-hexopyranose	C1CC2OCC(C1O)O2	560,102
	Decanoic acid, propyl ester	CCCCCCCCCC(= O)OCCC	121,739
8	6-Bromohexanoic acid, hexyl ester	CCCCCCOC(= O)CCCCCBr	543,783
	1,3-Hexanediol, 2-ethyl-	CCCC(C(CC)CO)O	7211
	1-Undecene, 2-methyl-	CCCCCCCCCC(= C)C	87,689
9	1,3-Dioxane, 2-ethyl-5-methyl-	CCC1OCC(CO1)C	141,976
	Silanol, trimethyl-, propanoate	CCC(= O)O[Si](C)(C)C	519,321
	.beta.-D-Ribopyranoside, methyl 2, 3,4-tri-O-methyl-	COC1COC(C(C1OC)OC)OC	21,140,439
10	Propane, 1-isothiocyanato-	CCCN = C = S	69,403
	Butane, 1,1′-[ethylidenebis(oxy)]bis-	CCC(C)COC(C)OCC(C)CC	551,340
11	1-Butoxy-1-isobutoxy-butane	CCCCOC(CCC)OCC(C)C	545,190
	Para methadione	CCC1(C(= O)N(C(= O)O1)C)C	8280
12	Butane, 1,1-dibutoxy-	CCCCOC(CCC)OCCCC	22,210
	1-Butoxy-1-isobutoxy-butane	CCCCOC(CCC)OCC(C)C	545,190
	Neopentyl isothiocyanate	CC(C)(C)CN = C = S	136,393

Table 5

GC–MS analysis of aqueous leaf of Vernonia amygdalina

S/N	Compound	Canonical SMILES	PubChem CID
1	Ethyl acetate	CCOC(= O)C	8857
2	2-Propenal	C = CC = O	7847
	2-Propen-1-amine	C = CCN	7853
3	2-Propenal	C = CC = O	7847
	Aziridine, 2-methyl-	CC1CN1	6377
4	Acetic acid, butyl ester	CCCCOC(= O)C	31,272
5	Ethanamine, N-pentylidene-	CCCCC = NCC	544,805
	2-Propanone, propylhydrazone	CCCNN = C(C)C	139,018
	Oxirane, (1-methylethyl)-	CC(C)C1CO1	102,618
6	Pyrazol-3(2H)-one, 4-(5-hydroxymethylfurfur-2-ylidenamino)-1,5-dimethyl-2-phenyl-	CC1 = C(C(= O)N(N1C)C2 = CC = CC = C2)N = CC3 = CC = C(O3)CO	544,706
	Ethylbenzene	CCC1 = CC = CC = C1	7500
7	n-Butyl ether	CCCCOCCCC	8909
	Formic acid, 3,3-dimethylbut-2-yl ester	CC(C(C)(C)C)OC = O	54,488,145
8	Ethane, 1-chloro-2-isocyanato-	C(CCl)N = C = O	16,035
	1-Hexene, 3,4-dimethyl-	CCC(C)C(C)C = C	140,134
	3,4,5-Trimethyldihydrofuran-2-one	CC1C(C(= O)OC1C)C	544,600
9	Cyclohexane acetic acid, butyleste
	Acetamide, N-cyclohexyl-	CC(= O)NC1CCCCC1	14,301
	Pentane, 1-bromo-3,4-dimethyl-	CC(C)C(C)CCBr	544,665
10	N-Cyclododecylacetamide	CC(= O)NC1CCCCCCCCCCC1	548,224
	Cyclohexaneacetic acid, butyl este
	Trisilane	C[Si](C)(C)[Si](C)(C)[Si](C)(C)C1 = CC = CC2 = CC = CC = C21	142,270
11	1,6-Anhydro-2,3-dideoxy-.beta.-D-erythro-hexopyranose	C1CC2OCC(C1O)O2	560,102
	2-Butenoic acid, butyl ester	CCCCOC(= O)C = CC	5,366,039
	Morpholine	C1COCCN1	8083
12	Dimethyl{bis[(3-methylbut-2-en-1-yl)oxy]}silane	CC(= CCO[Si](C)(C)OCC = C(C)C)C	91,697,225
	1-Propanol, 2,2-dimethyl-, acetate	CC(= O)OCC(C)(C)C	13,552
	Allyl(2-butoxy)dimethylsilane	CCC(C)O[Si](C)(C)CC = C	554,670
13	Succinic acid, hexyl 3-oxobut-2-yl-ester	CCCCCCOC(= O)CCC(= O)OC(C)C(= O)C	91,702,832
	.beta.-D-Xylopyranoside, methyl 2,3,4-tri-O-methyl-	COC1COC(C(C1OC)OC)OC2C(C(COC2OC)OC)OC	91,726,683
	Tridecyl (E)-2-methylbut-2-enoate	CCCCCCCCCCCCCOC(= O)C(= CC)C	91,701,893
14	Thiazole, 2-ethyl-4,5-dihydro-	CCC1 = NCCS1	86,896
	Cyclohexane, 1R-acetamido-2,3-cis-epoxy-4-cis-formyloxy-	CC(= O)NC1CCC(C2C1O2)OC = O	537,204
	Cyclopentane, 1-methyl-2-(4-methylpentyl)-, trans-	CC1CCCC1CCCC(C)C	6,432,631
15	Cyclopentaneundecanoic acid	C1CCC(C1)CCCCCCCCCCC(= O)O	534,549
	Cyclohexane, 1R-acetamido-2,3-cis-epoxy-4-cis-formyloxy-	CC(= O)NC1CCC(C2C1O2)OC = O	537,204
	Pentadecanoic acid	CCCCCCCCCCCCCCC(= O)O	13,849
16	Butane, 1,1-dibutoxy-	CCCCOC(CCC)OCCCC	22,210
	1-Butoxy-1-isobutoxy-butane	CCCCOC(CCC)OCC(C)C	545,190
17	Dodecanoic acid	CCCCCCCCCCCC(= O)O	3893
	Carbamic acid, [1-(hydroxymethyl)-2-phenylethyl]-, 1,1-dimethylethyl ester, (s)-	CC(C)(C)OC(= O)NC(CC1 = CC = CC = C1)CO	2,733,675
	8-Chlorocapric acid	C(CCCC(= O)O)CCCCl	548,250
18	Acetamide, N-cyclohexyl-2-[(2-furanylmethyl)thio]-	C1CCC(CC1)NC(= O)CSCC2 = CC = CO2	5,298,618
	n-Decanoic acid	CCCCCCCCCC(= O)O	2969
	Pentadecanoic acid	CCCCCCCCCCCCCCC(= O)O	13,849
19	Acetamide, N-cyclohexyl-2-[(2-furanylmethyl)thio]-	C1CCC(CC1)NC(= O)CSCC2 = CC = CO2	5,298,618
	Propane, 1,2-dichloro-2-fluoro-	CCCCCCCCCCCCCCC(= O)O	13,849
	1-Butyl-3,4-dihydroxy-pyrrolidine- 2,5-dione	CCCCN1C(= O)C(C(C1 = O)O)O	6,420,934
20	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
	Ethanol, 2-bromo-	C(CBr)O	10,898
21	Borolane, 3-ethyl-4-methyl-1,2,2-tris(1-methylethyl)-	B1(CC(C(C1(C(C)C)C(C)C)CC)C)C(C)C	535,085
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl	CC1CCC(C1CO)C(C)CO	101,710
22	Cyclohexanone, 2-(2-propenyl)-	C = CCC1CCCCC1 = O	78,944
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
23	Cyclohexanone, 2-(2-propenyl)-	C = CCC1CCCCC1 = O	78,944
	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	Cyclohexanone, 2-(1-mercapto-1-methylethyl)-5-methyl-, trans-	CC1CCC(C(= O)C1)C(C)(C)S	6,951,713
24	Cyclohexanone, 2-(1-mercapto-1-methylethyl)-5-methyl-, trans-	CC1CCC(C(= O)C1)C(C)(C)S	6,951,713
	Cyclohexanone, 2-(2-propenyl)-	C = CCC1CCCCC1 = O	78,944
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
25	1,4-Cyclohexanedimethanamine	C1CC(CCC1CN)CN	17,354
	Borolane, 3-ethyl-4-methyl-1,2,2-tris(1-methylethyl)-	B1(CC(C(C1(C(C)C)C(C)C)CC)C)C(C)C	535,085
	(4-Methoxymethoxy-hex-5-ynylidene)-cyclohexane	COCOC(CCC = C1CCCCC1)C#C	542,331
26	Cyclobutanone, 2-methyl-2-oxiranyl	COCOC(CCC = C1CCCCC1)C#C	542,331
	Borolane, 3-ethyl-4-methyl-1,2,2-tris(1-methylethyl)-	B1(CC(C(C1(C(C)C)C(C)C)CC)C)C(C)C	535,085
	Cyclohexanone, 2-(2-propenyl)-	C = CCC1CCCCC1 = O	78,944
27	Cyclobutanone, 2-methyl-2-oxiranyl	COCOC(CCC = C1CCCCC1)C#C	542,331
	3-Oxatricyclo[4.2.0.0(2,4)]octan-7-one	C1C2C(CC2 = O)C3C1O3	556,833
	1-Methoxy-3-(2-hydroxyethyl)nonane	CCCCCCC(CCO)CCOC	542,174
28	Cyclobutanone, 2-methyl-2-oxiranyl	COCOC(CCC = C1CCCCC1)C#C	542,331
	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
	3-Oxatricyclo[4.2.0.0(2,4)]octan-7-one	C1C2C(CC2 = O)C3C1O3	556,833
29	1-Methoxy-3-(2-hydroxyethyl)nonane	CCCCCCC(CCO)CCOC	542,174
	2-Tetradecanol	CCCCCCCCCCCCC(C)O	20,831
	2H-1,2,3-Triazol-4-amine, 2-cyclohexyl-5-nitro-, 1-oxide		249,914,956
30	1-Methoxy-3-(2-hydroxyethyl)nonane	CCCCCCC(CCO)CCOC	542,174
	3-Oxatricyclo[4.2.0.0(2,4)]octan-7-one	C1C2C(CC2 = O)C3C1O3	556,833
	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
31	Cyclohexanone, 2-(2-propenyl)-	C = CCC1CCCCC1 = O	78,944
	Oxonin, 4,5,6,7-tetrahydro-, (Z,Z)32
	1-Methoxy-3-(2-hydroxyethyl)nonane	CCCCCCC(CCO)CCOC	542,174
32	Cyclobutanone, 2-methyl-2-oxiranyl	CC1CCC(C1CO)C(C)CO	101,710
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
	3H-Naphth[1,8a-b]oxiren-2(1aH)-one, hexahydro-	C1CCC = COC = CC1	5,365,711
33	Cyclohexanone, 2-(2-propenyl)-	C = CCC1CCCCC1 = O	78,944
	(4-Methoxymethoxy-hex-5-ynylidene)25-cyclohexane	COCOC(CCC = C1CCCCC1)C#C	542,331
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138

Table 6

GC–MS analysis of aqueous bark of Anacardium occidentale

S/N	Compound	Canonical SMILES	PubChem CID
1	Ethyl acetate	CCOC(= O)C	8857
2	2-Propenal	C = CC = O	7847
	2-Propen-1-amine	C = CCN	7853
3	Acetic acid, butyl ester	CCCCOC(= O)C	31,272
4	Ethanamine, N-pentylidene-	CCCCC = NCC	544,805
	Acetaldehyde, butylhydrazone	CCCCNN = CC	9,601,789
	2-Propanone, propylhydrazone	CCCNN = C(C)C	139,018
5	p-Xylene	CC1 = CC = C(C = C1)C	7809
	o-Xylene	CC1 = CC = CC = C1C	7237
	Ethylbenzene	CCC1 = CC = CC = C1	7500
6	n-Butyl ether	CCCCOCCCC	8909
	Formic acid, 3,3-dimethylbut-2-yl ester	CC(C(C)(C)C)OC = O	54,488,145
	Ethanol, 2-butoxy-	CCCCOCCO	8133
7	Pyrazol-3(2H)-one, 4-(5-hydroxymethylfurfur-2-ylidenamino)-1,5-dimethyl-2-phenyl-	CC1 = C(C(= O)N(N1C)C2 = CC = CC = C2)N = CC3 = CC = C(O3)CO	544,706
	Ethane, 1-chloro-2-isocyanato-	C(CCl)N = C = O	16,035
	1-Oxa-4-azaspiro[4.5]decan-4-oxyl, 3,3-dimethyl-8-oxo-	CC1(COC2([N +]1 = O)CCC(= O)CC2)C	6,420,654
8	1-Octene, 2-methyl-	CCCCCCC(= C)C	78,335
	1-Pentene, 5-chloro-4-(chloromethyl)-2,4-dimethyl-	CC(= C)CC(C)(CCl)CCl	544,717
	4-t-Butylcyclohexylamine	CC(C)(C)C1CCC(CC1)N	79,396
9	Butane, 2,2′-thiobis-	C(CCO)CO.C(CSCCO)O	44,153,764
	Dimethylamine, N-(neopentyloxy)-	CC(C)(C)CON(C)C	548,341
	3-Deoxy-d-mannitol	C(C(CO)O)C(C(CO)O)O	560,035
10	Silane, trimethyl(2-methylpropoxy)	CC(C)CO[Si](C)(C)C	519,538
	1-Propanol, 2,2-dimethyl-, acetate	CC(= O)OCC(C)(C)C	13,552
	Propanoic acid, dimethyl(chloromethyl)silyl ester	CCC(= O)O[Si](C)(C)CCl	554,674
11	2-Butylthiazoline	CCCCC1 = NCCS1	206,597
	4.beta.,5-Dimethyl-6,8-dioxa-3-thiabicyclo(3,2,1)octane 3-oxide	CC1C2(OCC(O2)CS1 = O)C	538,769
	Succinic acid, butyl decyl ester	CCCCCCCCCCOC(= O)CCC(= O)OCCCC	91,701,657
12	1-Pentadecene, 2-methyl-	CCCCCCCCCCCCCC(= C)C	520,456
	Pyrido[2,3-d]pyrimidine, 4-phenyl-	C1 = CC = C(C = C1)C2 = C3C = CC = NC3 = NC = N2	610,177
	1-Benzenesulfonyl-1H-pyrrole	C1 = CC = C(C = C1)S(= O)(= O)N2C = CC = C2	140,146
13	Acetamide, N-(4-hydroxycyclohexyl) -, cis-	CC(= O)NC1CCC(CC1)O	90,074
	Octasiloxane, 1,1,3,3,5,5,7,7,9,9,11,11,13,13,15,15-hexadecamethyl-	C[Si](C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)C	6,329,087
	1H-Indole, 5-methyl-2-phenyl-	CC1 = CC2 = C(C = C1)NC(= C2)C3 = CC = CC = C3	83,247
14	Thiazole, 2-ethyl-4,5-dihydro-	CCC1 = NCCS1	86,896
	Cyclohexane, 1R-acetamido-2,3-cis-epoxy-4-cis-formyloxy-	CC(= O)NC1CCC(C2C1O2)OC = O	537,204
	Cyclopentaneundecanoic acid	C1CCC(C1)CCCCCCCCCCC(= O)O	534,549
15	Cyclopentaneundecanoic acid	C1CCC(C1)CCCCCCCCCCC(= O)O	534,549
	Cyclohexane, 1R-acetamido-2,3-cis-epoxy-4-cis-formyloxy-	CC(= O)NC1CCC(C2C1O2)OC = O	537,204
	Decanoic acid, silver(1 +) salt		319,368,662
16	Butane, 1,1-dibutoxy-	CCCCOC(CCC)OCCCC	22,210
	1-Butoxy-1-isobutoxy-butane	CCCCOC(CCC)OCC(C)C	545,190
	Neopentyl isothiocyanate	CC(C)(C)CN = C = S	136,393
17	Nonanoic acid	CCCCCCCCC(= O)O	8158
	.alpha.-D-Glucopyranose, 4-O-.beta.-D-galactopyranosyl	C(C1C(C(C(C(O1)OC2C(OC(C(C2O)O)O)CO)O)O)O)O.O	522,113
	n- Decanoic acid	CCCCCCCCCC(= O)O	2969
18	Tridecanoic acid	CCCCCCCCCCCCC(= O)O	12,530
	Octasiloxane, 1,1,3,3,5,5,7,7,9,9,11,11,13,13,15,15-hexadecamethyl-	C[Si](C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)C	6,329,087
19	Z,E-7,11-Hexadecadien-1-yl acetate	CCCCC = CCCC = CCCCCCCOC(= O)C	5,363,282
	2(1H)-Naphthalenone, octahydro-4a- methyl-7-(1-methylethyl)-, (4a.alp ha.,7.beta.,8a.beta.) -
	3,6-Epoxy-2H,8H-pyrimido[6,1-b][1,3]oxazocine-8,10(9H)-dione, 4-(ace tyloxy)-3,4,5,6-tetrahydro-11-meth yl-, [3R-(3.alpha.,4.beta.,6.alpha .)]-
20	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
	Chloroacetic acid, 1-cyclopentylethyl ester	CC(C1CCCC1)OC(= O)CCl	543,343
	Dodecanoic acid, 1,2,3-propanetriyl ester	CCCCCCCCCCCC(= O)OCC(COC(= O)CCCCCCCCCCC)OC(= O)CCCCCCCCCCC	10,851
21	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
	3H-Naphth[1,8a-b]oxiren-2(1aH)-one, hexahydro-	C1CCC = COC = CC1	5,365,711
	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
22	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
	Spiro[2.3]hexan-4-one, 5,5-diethyl	CC1(CC2(C1 = O)CC2)C	534,214
23	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
	3-Oxatricyclo[4.2.0.0(2,4)]octan-7-one	C1C2C(CC2 = O)C3C1O3	556,833
	Cyclobutanone, 2-methyl-2-oxiranyl	CC1CCC(C1CO)C(C)CO	101,710
24	Cyclobutanone, 2-methyl-2-oxiranyl	CC1CCC(C1CO)C(C)CO	101,710
	1-Methoxy-3-(2-hydroxyethyl)nonane	CCCCCCC(CCO)CCOC	542,174
	Cyclohexanone, 2-(2-propenyl)-	C = CCC1CCCCC1 = O	78,944
25	3-Oxatricyclo[4.2.0.0(2,4)]octan-7-one	C1C2C(CC2 = O)C3C1O3	556,833
	1-Methoxy-3-(2-hydroxyethyl)nonane	CCCCCCC(CCO)CCOC	542,174
	Cyclobutanone, 2-methyl-2-oxiranyl	CC1CCC(C1CO)C(C)CO	101,710
26	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
	Chloroacetic acid, 1-cyclopentylethyl ester	CC(C1CCCC1)OC(= O)CCl	543,343
27	1-Methoxy-3-(2-hydroxyethyl)nonane	CCCCCCC(CCO)CCOC	542,174
	Cyclohexanone, 2-(2-propenyl)-	C = CCC1CCCCC1 = O	78,944
	3-Oxatricyclo[4.2.0.0(2,4)]octan-7-one	C1C2C(CC2 = O)C3C1O3	556,833
28	Cyclobutanone, 2-methyl-2-oxiranyl	CC1CCC(C1CO)C(C)CO	101,710
	1-Methoxy-3-(2-hydroxyethyl)nonane	CCCCCCC(CCO)CCOC	542,174
	2-Butynamide, N-methyl-	CC#CC(= O)NC	549,138
29	Dodecanoic acid, 1,2,3-propanetriyl ester	CCCCCCCCCCCC(= O)OCC(COC(= O)CCCCCCCCCCC)OC(= O)CCCCCCCCCCC	10,851
	[1,2,4]Triazolo[1,5-a]pyrimidin-5(4H)-one, 7-amino-4-methyl-	CN1C(= O)C = C(N2C1 = NC = N2)N	16,766,882
30	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
	1-Methoxy-3-(2-hydroxyethyl)nonane	CCCCCCC(CCO)CCOC	542,174
	Cyclobutanone, 2-methyl-2-oxiranyl	CC1CCC(C1CO)C(C)CO	101,710
31	Dodecanoic acid, 1,2,3-propanetriyl ester	CCCCCCCCCCCC(= O)OCC(COC(= O)CCCCCCCCCCC)OC(= O)CCCCCCCCCCC	10,851
	Cyclododecanol, 1-aminomethyl-	C1CCCCCC(CCCCC1)(CN)O	533,851
	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
32	Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	CC1CCC(C1CO)C(C)CO	101,710
	1-Methoxy-3-(2-hydroxyethyl)nonane	CCCCCCC(CCO)CCOC	542,174
	Cyclobutanone, 2-methyl-2-oxiranyl	CC1CCC(C1CO)C(C)CO	101,710
33	Cyclododecanol, 1-aminomethyl-	C1CCCCCC(CCCCC1)(CN)O	533,851
	1H-Imidazole, 2-ethyl-4,5-dihydro-	CCC1 = NCCN1	13,590
	1-Phenyloxycarbonyl-7-pentyl-7-aza bicyclo[4.1.0]heptane

Fig. 7

GC–MS spectrum of aqueous leaf of Azadirachta indica

Fig. 8

GC–MS spectrum of aqueous leaf of Corchorus olitorius

Fig. 9

GC–MS spectrum of aqueous leaf of Cassia alata

Fig. 10

GC–MS spectrum of aqueous leaf of Phyllanthus amarus

Fig. 11

GC–MS spectrum of aqueous leaf of Vernonia amygdalina

Fig. 12

GC–MS spectrum of aqueous bark of Anacardium occidentale

Molecular docking analysis

The molecular docking analysis and visualization of the selected proteins of Coronavirus-2 with the phytochemicals identified from the six medicinal plants (Azadirachta indica, Corchorus olitorius, Cassia alata, Phyllanthus amarus, Vernonia amygdalina, and Anacardium occidentale) were showed in Tables 7, 8, 9, 10, 11 and 12. The results revealed that the phytochemicals demonstrated high binding affinities against the proteins. This indicates that these phytochemicals could have substantial inhibitory effects against these proteins thus mitigating their pathogenic properties, ultimately leading to suppression of the pathogenesis of COVID-19.

Table 7

Molecular docking score of the phytochemicals of Azadirachta indica against proteins of Coronavirus-2

Phytochemicals	2AJF	6LU7	6VXS	7BTF
	Binding energies (kcal/mol)	Binding energies (kcal/mol)	Binding energies (kcal/mol)	Binding energies (kcal/mol)
(4-Methoxymethoxy-hex-5-ynylidene) -cyclohexane	− 5.8	− 4.3	− 5.1	− 4.8
1,1-Di(isobutyl)acetone	− 5.5	− 4.9	− 5	− 5.6
1,1-Diisobutoxy-isobutane	− 4.9	− 4.8	− 5	− 5.2
1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane	− 7	− 6.4	− 7.3	− 7.8
1,4-Cyclohexanedimethanamine	− 4.9	− 4.6	− 4.7	− 4.7
1-Butoxy-1-isobutoxy-butane	− 4.6	− 4	− 4.5	− 4.5
Ethane, 1-chloro-2-isocyanato-	− 3.4	− 3.3	− 3	− 3.8
1-Methoxymethoxy-oct-2-yne	− 4.9	− 3.9	− 3.9	− 4.6
1-Pentadecyne	− 4.2	− 3.6	− 4.1	− 4.3
Cyclohexanol, 1R-4-acetamido-2,3-cis-epoxy-	− 5.3	− 5.1	− 4.7	− 4.8
1RA23A_Cyclohexanol	− 5.5	− 5.2	− 4.8	− 5.1
Butane, 2,2′-thiobis-	− 3.8	− 3.4	− 4	− 4
2-Butynamide, N-methyl-	− 4.5	− 3.5	− 3.8	− 4.3
1-Heptene, 2-methyl-	− 5	− 3.6	− 3.9	− 4.5
3-Hexanone, 2-methyl-	− 4.4	− 3.8	− 3.9	− 4.6
2_methylphenylester	− 5.9	− 6.1	− 6.2	− 6.4
2-Nonanone	− 4.4	− 3.8	− 4.1	− 4.7
2-Propen-1-amine	− 3.4	− 3.3	− 2.9	− 3.5
2-Propenal	− 3	− 2.6	− 2.4	− 3.2
3,4-Dimethylpent-2-en-1-ol	− 4.5	− 4.4	− 4.2	− 4.7
3_Hydroxy_3_trifluoromethyl_2_oxa_ spiro[5_5]undecan_5_one	− 7.1	− 6.3	− 6.5	− 6.9
3H-Naphth[1,8a-b]oxiren-2(1aH)-one, hexahydro-	− 5.8	− 5.3	− 5.2	− 6.1
4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester_yl)_3_5_dimethyl_1H_pyrrole_2_carboxylic acid ethyl ester	− 6.8	− 7.6	− 7.9	− 7.5
4a-Methyl-6,8-dioxa-3-thia-bicyclo(3,2,1)octane	− 4.1	− 4	− 3.6	− 4.1
5_Methoxymethoxyhexa_2_3_diene	− 4.1	− 3.4	− 3.7	− 4.2
9,12-Octadecadienoic acid (Z,Z)-	− 7.3	− 5.9	− 7.3	− 6.4
beta.-D-Ribopyranoside, methyl 2, 3,4-tri-O-methyl-	− 4.2	− 4.1	− 3.8	− 4.2
Butane, 1,1-dibutoxy-	− 4.3	− 3.9	− 4.3	− 4.2
Chloroacetic acid	− 3	− 3.1	− 3	− 3.9
Chloroacetic acid, 1-cyclopentylet hyl ester	− 5.1	− 4.4	− 4.8	− 5.2
Chloromethyl octyl ether	− 4.6	− 3.7	− 4.1	− 4.5
Cyclohexane, 1R-acetamido-2,3-cis-epoxy-4-cis-formyloxy-	− 5.7	− 4.9	− 5.4	− 5.1
Cyclohexanol_ 2_(2_propynyloxy)__ trans_	− 5.2	− 4.4	− 5.1	− 4.7
Cyclohexanone, 2-(2-propenyl)-	− 5.3	− 4.6	− 4.7	− 6
Dodecanoic acid	− 6.4	− 4.8	− 5.6	− 6
Ethyl Acetate	− 3.7	− 3.3	− 2.8	− 3.8
Ethylbenzene	− 6.1	− 4.4	− 4.5	− 5.5
Furo[′,3′:4,5]thiazolo[3,2-g]purine-8-methanol, 4-amino-6.alpha.,7,8,9a-tetrahydro-7-hydroxy-, [6aS(6a.alpha.,7.alpha.,8.beta.,9a.alpha.)]-	− 6	− 6.1	− 5.4	− 6.4
Hexadecanoic acid, 3,7,11,15-tetramethyl-, methyl ester	− 6.5	− 5.5	− 5.8	− 6.1
Methyl 6_O_[1_methylpropyl]__beta_ _d_galactopyranoside	− 5.6	− 5.7	− 5.6	− 5.7
n-Butyl ether	− 4	− 3.6	− 3.8	− 3.7
n-Decanoic acid	− 5.9	− 5	− 5.5	− 5.4
N1,N1-Dimethyl-N2-(1-phenyl–ethyl) -ethane-1,2-diamine	− 6.3	− 5.6	− 5.5	− 5.7
Nonanoic acid	− 5.5	− 4.8	− 5.2	− 5
o-Xylene	− 6.4	− 4.6	− 4.5	− 5.7
Propanoic acid	− 3.6	− 3.2	− 3.1	− 4.1
Thioctic acid	− 5.3	− 4.6	− 4.9	− 5
Undec-10-ynoic acid	− 5.6	− 4.9	− 5.5	− 5.5

Table 8

Molecular docking analysis of the phytochemicals of Corchorus olitorius against proteins of Coronavirus-2

Phytochemicals	2AJF	6LU7	6VXS	7BTF
	Binding energies (kcal/mol)	Binding energies (kcal/mol)	Binding energies (kcal/mol)	Binding energies (kcal/mol)
1,1-Cyclohexanedicarbonitrile	− 5.1	− 5.1	− 4.6	− 5.4
1-Butoxy-1-isobutoxy-butane	− 4.8	− 4.6	− 4.7	− 4.8
Ethane, 1-chloro-2-isocyanato-	− 3.6	− 3.3	− 3	− 3.9
Tridecyl (E)-2-methylbut-2-enoate	− 3.6	− 3.1	− 3.2	− 3.5
11-Bromoundecanoic acid	− 6	− 4.9	− 5.4	− 5.6
12, 12-Dimethoxydodecanoic acid, methyl ester	− 5.1	− 4	− 4.5	− 4.4
2-Ethylacridine	− 7	− 6.4	− 6.9	− 7.1
3-Hexanone, 2-methyl-	− 4.7	− 3.8	− 3.9	− 4.5
2-Propen-1-amine	− 3.1	− 3.3	− 2.9	− 3.1
2-Propenal	− 2.9	− 2.6	− 2.4	− 3.2
3_4_dihydroxy_1_Butyl	− 3.8	− 4	− 3.4	− 4.1
3-Phenylpropionic acid, 4-methoxy- 2-methylbutyl ester	− 5.7	− 4.9	− 5.7	− 6.1
4-Ethyl-4-methyl-5-methylene-[1,3] dioxolan-2-one	− 4.8	− 4.4	− 4.1	− 5
9-Bromononanoic acid	− 5.5	− 4.4	− 5.3	− 5.9
Acetamide, N-(4-hydroxycyclohexyl) -, cis-	− 5.6	− 4.8	− 5	− 4.9
Acetamide, N-cyclohexyl-	− 4.9	− 4.3	− 5	− 5.1
Acetamide, N-cyclohexyl-2-[(2-furanylmethyl)thio]-	− 5.9	− 5.2	− 5.5	− 5.8
Acetic acid_ butyl ester	− 3.8	− 3.4	− 3.5	− 4.2
Acetic acid_ pentyl ester	− 4.1	− 3.6	− 3.9	− 4.6
Benzene, 1,3-dimethyl-	− 6.2	− 4.7	− 4.8	− 5.6
Butane, 1, 1-dibutoxy-	− 4.7	− 4	− 4.2	− 4
Butyric acid, 2,2-dimethyl-vinyl ester	− 4.2	− 4.2	− 4	− 4.8
ethyl Acetate	− 3.1	− 2.9	− 2.8	− 3.7
Formic acid, 3,3-dimethylbut-2-yl ester	− 4	− 3.9	− 3.8	− 4.3
Hexadecane, 1, 1- dimethoxy-	− 4.8	− 3.8	− 4.5	− 4.5
Isopropyl isothiocyanate	− 3.3	− 3.4	− 3.1	− 3.6
L-Lyxose	− 4.3	− 4.9	− 4
n-Butyl ether	− 3.8	− 3.6	− 3.9	− 3.6
N-Cyclododecylacetamide	− 6.3	− 6	− 5.8	− 6.3
o-Xylene	− 5.2	− 4.6	− 4.8	− 5.6
Octadecanoic acid	− 7	− 5.7	− 4.5	− 6.9
pyrrolidine_ 2_5_dione	− 4.4	− 4	− 5.9	− 4.7
Tridecyl (E)_2_methylbut_2_enoate	− 4.5	− 3.9	− 3.9	− 4.8

Table 9

Molecular docking analysis of the phytochemicals of Cassia alata against proteins of Coronavirus-2

Phytochemicals	2AJF	6LU7	6VXS	7BTF
	Binding energies (kcal/mol)	Binding energies (kcal/mol)	Binding energies (kcal/mol)	Binding energies (kcal/mol)
1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane	− 6.9	− 6.3	− 7.2	− 7.8
1-Butoxy-1-isobutoxy-butane	− 4.6	− 4.2	− 4.5	− 4.4
1-Oxa-4-azaspiro[4.5]decan-4-oxyl, 3,3-dimethyl-8-oxo-	− 5.5	− 5.2	− 5.1	− 5.6
2-Octanol, 8,8-dimethoxy-2,6-dimethyl-	− 5.4	− 4.9	− 5.2	− 5.4
3-Hexanone, 2-methyl-	− 4.4	− 3.8	− 3.9	− 4.5
6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2_methylsulfanyl_ethyl ester	− 7.1	− 6.9	− 7.5	− 7.2
Acetaldehyde, butylhydrazone	− 4.3	− 3.6	− 3.8	− 4.5
Acetic acid, butyl ester	− 4.2	− 3.4	− 3.6	− 4.2
Butane, 1, 1-dibutoxy-	− 4.5	− 3.9	− 4.3	− 4.3
Butyric acid, 2, 2-dimethyl-, vinyl ester	− 4.2	− 4.2	− 4	− 4.4
Cyclohexane, 1R-acetamido-2,3-cis-epoxy-4-cis-formyloxy-	− 5.6	− 4.9	− 5.4	− 5.8
Cyclohexaneacetic acid, butyl ester	− 5.2	− 4.1	− 5.2	− 5.4
Cyclopentaneundecanoic acid	− 7.6	− 5.6	− 6.6	− 6.3
D-Arabinitol	− 4.4	− 5.2	− 4	− 4.5
Ethanol, 2-phenoxy-, propanoate	− 5.1	− 4.5	− 5.2	− 5.6
Furo[2′,3′:4,5]thiazolo[3,2-g]purine-8-methanol, 4-amino-6.alpha.,7,8,9a-tetrahydro-7-hydroxy-, [6aS-(6a.alpha.,7.alpha.,8.beta.,9a.alph a.)]-	− 5.9	− 6.1	− 5.4	− 6.4
Hexyl 2-hydroxyethyl sulfide	− 4.6	− 4.5	− 4.4	− 4.5
n-Butyl ether	− 4.1	− 3.5	− 3.9	− 3.6
o-Xylene	− 5.3	− 4.6	− 4.5	− 5.7
Paramethadione	− 4.7	− 4.5	− 4.3	− 4.9
Propanoic acid, 2-methylpropyl ester	− 4.2	− 3.7	− 4	− 4.6
Pyrazol-3(2H)-one, 4-(2-furfurylidenamino)-1,5-dimethyl-2-phenyl-	− 6.4	− 6.9	− 6.8	− 6.5
Ribitol	− 5	− 5.2	− 4.8	− 5
Tridecyl (E)-2-methylbut-2-enoate	− 5.1	− 4.2	− 4.7	− 5.4

Table 10

Molecular docking analysis of the phytochemicals of Phyllanthus amarus against proteins of Coronavirus-2

Phytochemicals	2AJF	6LU7	6VXS	7BTF
	Binding energies (kcal/mol)	Binding energies (kcal/mol)	Binding energies (kcal/mol)	Binding energies (kcal/mol)
1,3-Dioxane, 2-ethyl-5-methyl-	− 4.2	− 3.9	− 4	− 4.1
1, 3-Hexanediol, 2-ethyl-	− 4.8	− 4.7	− 4.5	− 4.6
1,6-Anhydro-2,3-dideoxy-.beta.-D-erythro-hexopyranose	− 4.9	− 4.5	− 4.1	− 4.8
1-Butoxy-1-isobutoxy_-butane	− 4.6	− 4.4	− 4.7	− 4.6
1-Hexene, 3, 4-dimethyl-	− 4.7	− 4.2	− 4.1	− 5
1-Undecene, 2-methyl-	− 5	− 3.9	− 4.5	− 4.3
2,4-Dipropyl-5-ethyl-1,3-dioxane	− 5	− 4.6	− 4.7	− 4.8
2_Methylvaleroyl chloride	− 4.3	− 4.1	− 3.8	− 4.4
2H-Pyran-2-one, tetrahydro-5,6-dimethyl-, trans-	− 4.9	− 4.2	− 4.2	− 5.4
3-Hexanone, 2-methyl-	− 4.4	− 3.8	− 3.9	− 4.5
6-Bromohexanoic acid, hexyl ester	− 5	− 3.8	− 4.7	− 4.6
Acetic acid, butyl ester	− 3.7	− 3.3	− 3.5	− 4.2
Butane, 1,1′-[ethylidenebis(oxy)]bis-	− 4.2	− 3.7	− 4.2	− 4.3
Butane, 1,1-dibutoxy-	− 4.5	− 3.8	− 4.1	− 4.1
Butanoic acid, butyl ester	− 4	− 3.7	− 4.1	− 4.2
Butyric acid, 2,2-dimethyl-, vinylester	− 4.4	− 4.2	− 4	− 4.5
Cyclododecylamine	− 6	− 5.2	− 5.5	− 6
Decanoic acid, propyl ester	− 4.8	− 4.1	− 4.2	− 4.4
Formic acid, 3,3-dimethylbut-2-ylester	− 4.1	− 3.9	− 3.8	− 4.1
n-Butyl ether	− 4	− 3.6	− 3.7	− 3.7
n-Butyl isobutyl sulfide	− 3.8	− 3.5	− 4	− 3.9
Neopentyl isothiocyanate	− 4.3	− 3.8	− 3.7	− 3.8
o-Xylene	− 6.4	− 4.6	− 4.5	− 5.6
Pentane, 1-bromo-3,4-dimethyl-	− 4.3	− 4.1	− 4	− 4.7
Pentane, 2,3-dimethyl-	− 4.4	− 3.7	− 3.8	− 4.8
Propane, 1-isothiocyanato-	− 3.4	− 3.2	− 3.2	− 3.3

Table 11

Molecular docking analysis of the phytochemicals of Vernonia amygdalina against proteins of Coronavirus-2

Phytochemicals	2AJF	6LU7	6VXS	7BTF
	Binding energies (kcal/mol)	Binding energies (kcal/mol)	Binding energies (kcal/mol)	Binding energies (kcal/mol)
(4-Methoxymethoxy-hex-5-ynylidene)-cyclohexane	− 5.5	− 4.6	− 5.4	− 5.3
.beta.-D-Xylopyranoside, methyl 2,3,4-tri-O-methyl-	− 3.8	− 4	− 3.8	− 4.5
1,4-Cyclohexanedimethanamine	− 4.9	− 4.7	− 4.7	− 4.6
1,6-Anhydro-2,3-dideoxy-.beta.-D-erythro-hexopyranose	− 4.9	− 4.5	− 4.1	− 4.7
1-Butoxy-1-isobutoxy-butane	− 4.3	− 3.9	− 4.7	− 4.6
1-Butyl-3,4-dihydroxy-pyrrolidine- 2,5-dione	− 5.3	− 5.1	− 4.8	− 6.2
1-Hexene, 3,4-dimethyl-	− 4.7	− 4.2	− 4.1	− 5
1-Methoxy-3-(2-hydroxyethyl)nonane	− 5.3	− 4.9	− 5	− 5.7
1_Propanol_ 2_2_dimethyl__ acetate	− 4.1	− 3.8	− 3.8	− 4.3
2-Butenoic acid, butyl ester	− 4.3	− 3.7	− 3.9	− 4
2-Butynamide, N-methyl-	− 4.1	− 3.5	− 3.8	− 4.7
2-Propanone, propylhydrazone	− 4.2	− 3.7	− 4.1	− 4.2
2-Propen-1-amine	− 3.1	− 3	− 2.9	− 3.4
2-Propenal	− 3	− 2.6	− 2.4	− 3.2
2-Tetradecanol	− 6.4	− 5.1	− 5.9	− 6.1
2H-1,2,3-Triazol-4-amine, 2-cyclohexyl-5-nitro-, 1-oxide	− 6.4	− 5.6	− 5.9	− 6.6
3,4,5-Trimethyldihydrofuran-2-one	− 4.5	− 4.2	− 4.1	− 5.1
3-Oxatricyclo[4.2.0.0(2,4)]octan-7-one	− 4.7	− 4.5	− 4.4	− 5.1
3H-Naphth[1,8a-b]oxiren-2(1aH)-one, hexahydro-	− 5.8	− 5.3	− 5.2	− 5.9
8-Chlorocapric acid	− 5.7	− 5.1	− 5.3	− 5.3
Acetamide, N-cyclohexyl-	− 5.3	− 4.3	− 5	− 5
Acetamide, N-cyclohexyl-2-[(2-furanylmethyl)thio]-	− 5.9	− 5.6	− 5.4	− 6
Acetic acid, butyl ester	− 3.7	− 3.2	− 3.5	− 4
Aziridine, 2-methyl-	− 3.3	− 2.6	− 2.7	− 3.3
Butane, 1,1-dibutoxy-	− 4.2	− 3.7	− 4.1	− 4.1
Carbamic acid, [1-(hydroxymethyl)-2-phenylethyl]-, 1,1-dimethylethyl ester, (s)-	− 6.1	− 6.2	− 5.7	− 6.6
Cyclobutanone, 2-methyl-2-oxiranyl	− 4.3	− 4	− 3.9	− 4.5
Cyclohexane acetic acid, butyleste	− 5.4	− 4.4	− 5.2	− 4.8
Cyclohexane, 1R-acetamido-2,3-cis-epoxy-4-cis-formyloxy-	− 5.2	− 4.9	− 5.4	− 5.1
Cyclohexaneacetic acid_ butyl ester	− 5.6	− 4.6	− 5.2	− 5.1
Cyclohexanone, 2-(1-mercapto-1-methylethyl)-5-methyl-, trans-	− 5.2	− 5.3	− 5.1	− 5.7
Cyclohexanone, 2-(2-propenyl)-	− 5.1	− 4.5	− 4.7	− 5.4
Cyclopentane, 1-methyl-2-(4-methylpentyl)-, trans-	− 5.4	− 4.8	− 5.1	− 5.5
Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	− 5.2	− 4.8	− 5.1	− 5.3
Cyclopentaneundecanoic acid	− 7.7	− 5.9	− 6.8	− 6.3
Dodecanoic acid	− 6.5	− 5.1	− 5.4	− 5.3
Ethanamine, N-pentylidene-	− 3.9	− 3.3	− 3.8	− 3.6
Ethane, 1-chloro-2-isocyanato-	− 3.5	− 3.3	− 3	− 3.8
Ethanol, 2-bromo-	− 2.9	− 2.9	− 2.7	− 3.3
Ethyl Acetate	− 3.5	− 3	− 2.9	− 3.9
Ethylbenzene	− 6.1	− 4.4	− 4.5	− 5.5
Formic acid, 3,3-dimethylbut-2-yl ester	− 4.1	− 3.9	− 3.8	− 4.2
Morpholine	− 3.2	− 3.3	− 3	− 4.2
n-Butyl ether	− 4.1	− 3	− 3.7	− 4.5
N-Cyclododecylacetamide	− 6.4	− 6	− 5.8	− 6.4
n-Decanoic acid	− 6.1	− 4.9	− 5.6	− 5.9
Oxirane, (1-methylethyl)-	− 3.5	− 3.2	− 4.8	− 3.7
Oxonin, 4,5,6,7-tetrahydro-, (Z,Z)32	− 4.9	− 4.6	− 3.3	− 5.4
Pentadecanoic acid	− 6.8	− 5.3	− 4.3	− 6.2
Pentane, 1-bromo-3,4-dimethyl-	− 4.3	− 4.1	− 5.9	− 4.7
Propane, 1,2-dichloro-2-fluoro-	− 3.7	− 3.6	− 4	− 3.7
Pyrazol-3(2H)-one, 4-(5-hydroxymethylfurfur-2-ylidenamino)-1,5-dimethyl-2-phenyl-	− 6.7	− 6.7	− 3.6	− 6.3
Succinic acid, hexyl 3-oxobut-2-yl-ester	− 4.7	− 4.1	− 6.7	− 5.5
Thiazole, 2-ethyl-4,5-dihydro-	− 3.7	− 3.2	− 4.8	− 3.7
Tridecyl (E)-2-methylbut-2-enoate	− 5.5	− 4.3	− 3.3	− 5.1

Table 12

Molecular docking analysis of the phytochemicals of Anacardium occidentale against proteins of Coronavirus-2

Phytochemicals	2AJF	6LU7	6VXS	7BTF
	Binding energies (kcal/mol)	Binding energies (kcal/mol)	Binding energies (kcal/mol)	Binding energies (kcal/mol)
.alpha.-D-Glucopyranose, 4-O-.beta.-D-galactopyranosyl	− 6.3	− 6.4	− 6.3	− 6.2
1-Benzenesulfonyl-1H-pyrrole	− 6.7	− 5.6	− 5.6	− 6
1-Butoxy-1-isobutoxy-butane	− 4.6	− 4.1	− 4.6	− 4.4
1-Methoxy-3-(2-hydroxyethyl)nonane	− 5.7	− 4.8	− 5	− 5.6
1-Octene, 2-methyl-	− 4.2	− 3.7	− 4.1	− 4.6
1-Oxa-4-azaspiro[4.5]decan-4-oxyl, 3,3-dimethyl-8-oxo-	− 5.1	− 5.3	− 5.2	− 6
1-Pentadecene, 2-methyl-	− 5.6	− 3.8	− 4.6	− 4.8
1-Pentene, 5-chloro-4-(chloromethyl)-2,4-dimethyl-	− 4.9	− 4	− 4.2	− 4.7
1-Phenyloxycarbonyl-7-pentyl-7-aza bicyclo[4.1.0]heptane	− 6.4	− 6	− 6.7	− 6.2
1-Propanol,2,2-dimethyl- acetate	− 4	− 3.9	− 3.7	− 4.3
1H-Imidazole, 2-ethyl-4,5-dihydro-	− 4.3	− 3.6	− 3.5	− 4.6
1H-Indole, 5-methyl-2-phenyl-	− 6.9	− 7.2	− 7.4	− 7.1
2(1H)-Naphthalenone, octahydro-4a- methyl-7-(1-methylethyl)-, (4a.alp ha.,7.beta.,8a.beta.) -	− 6.2	− 6	− 6.2	− 6.7
2-Butylthiazoline	− 4.1	− 3.7	− 3.7	− 4
2-Butynamide, N-methyl-	− 4.1	− 3.5	− 3.8	− 4.3
2-Propanone, propylhydrazone	− 4.2	− 3.6	− 4.1	− 4.3
2-Propen-1-amine	− 3.4	− 3	− 2.9	− 3.5
3-Oxatricyclo[4.2.0.0(2,4)]octan-7-one	− 4.7	− 4.5	− 4.4	− 5.1
3H-Naphth[1,8a-b]oxiren-2(1aH)-one, hexahydro-	− 5.8	− 5.3	− 5.3	− 6.1
4.beta.,5-Dimethyl-6,8-dioxa-3-thiabicyclo(3,2,1)octane 3-oxide	− 4.7	− 4.6	− 4.1	− 4.7
4-t-Butylcyclohexylamine	− 5.6	− 5.1	− 5.3	− 5.7
Acetaldehyde, butylhydrazone	− 4.4	− 3.8	− 3.8	− 4.2
Acetamide, N-(4-hydroxycyclohexyl) -, cis-	− 5.6	− 4.9	− 5	− 5.1
Acetic acid, butyl ester	− 3.9	− 3.4	− 3.5	− 3.8
Butane, 1,1-dibutoxy-	− 4.2	− 3.7	− 4.3	− 4
Butane, 2,2′-thiobis-	− 4	− 3.5	− 3.8	− 4.2
Chloroacetic acid, 1-cyclopentylethyl ester	− 5.2	− 4.5	− 4.7	− 5.2
Cyclobutanone, 2-methyl-2-oxiranyl	− 4.3	− 4.1	− 3.9	− 4.5
Cyclododecanol, 1-aminomethyl-	− 6.1	− 5.8	− 6.1	− 6.8
Cyclohexane, 1R-acetamido-2,3-cis-epoxy-4-cis-formyloxy-	− 5.8	− 4.9	− 5.4	− 5.3
Cyclohexanone, 2-(2-propenyl)-	− 4.9	− 4.4	− 4.7	− 5.9
Cyclopentaneethanol, 2-(hydroxymethyl)-.beta.,3-dimethyl-	− 5.2	− 4.8	− 5.1	− 5.2
Cyclopentaneundecanoic acid	− 7.3	− 5.7	− 6.6	− 7.2
Dimethylamine, N-(neopentyloxy)-	− 3.8	− 3.7	− 3.6	− 4.2
Dodecanoic acid, 1,2, 3-propanetriyl ester	− 5.5	− 3.9	− 4.5	− 5
Ethanamine, N-pentylidene-	− 3.8	-3.3	− 3.8	− 4.6
Ethane, 1-chloro-2-isocyanato-	− 3.4	− 3	− 3	− 3.8
Ethanol, 2-butoxy-	− 4.2	− 3.6	− 3.8	− 4.1
Ethyl Acetate	3.3	− 3.2	− 2.8	− 3.7
Ethylbenzene	− 6.1	− 4.4	− 4.5	− 5.5
Formic acid, 3,3-dimethylbut-2-yl ester	− 3.9	− 3.8	− 3.8	− 4.2
n-Butyl ether	− 4	− 3.4	− 3.8	− 3.8
n-decanoic acid	− 5.8	− 4.9	− 5.6	− 6
Neopentyl isothiocyanate	− 3.8	− 3.6	− 3.7	− 3.9
Nonanoic acid	− 5.5	− 4.8	− 5	− 5.2
o-Xylene	− 5.2	− 4.6	− 4.5	− 5.7
p-Xylene	− 6.1	− 4.5	− 4.5	− 5.6
Pyrazol-3(2H)-one, 4-(5-hydroxymethylfurfur-2-ylidenamino)-1,5-dimethyl-2-phenyl-	− 6.7	− 6.7	− 6.7	− 6.6
Pyrido[2,3-d]pyrimidine, 4-phenyl-	− 6.8	− 6.3	− 6.6	− 7
Spiro[2.3]hexan-4-one, 5,5-diethyl	− 4.6	− 4.1	− 4.5	− 4.9
Succinic acid,butyl decyl ester	− 5.4	− 4.2	− 4.7	− 4.8
Thiazole, 2-ethyl-4,5-dihydro-	− 3.4	− 3.2	− 3.3	− 3.5
Tridecanoic acid	− 6.5	− 5.1	− 6	− 6
Z,E-7,11-Hexadecadien-1-yl acetate	− 5.7	− 4.5	− 5	− 5.2

Molecular docking analysis of SARS coronavirus spike receptor-binding domain (2AJF)

The in silico analysis of 2AJF binding with the best ligands with the highest docking scores is shown in Fig. 13, Fig. 14, and Table 13. Out of the investigated phytochemicals from Azadirachta indica, 9,12-Octadecadienoic acid (Z,Z)- exhibited the best docked score (− 7.3 kcal/mol) with the SARS coronavirus spike receptor-binding domain (2AJF). The amino acid residues- ALA-348, SER-44, PHE-40, PHE-390, ASN-394, TRP-349, GLU-37, GLY-352, ASP-350, LEU-351, and ARG-393 participated extensively in the interaction at the binding pocket of 2AJF. N-Cyclododecylacetamide from Corchorus olitorius displayed the best docked score (− 6.4 kcal/mol) with 2AJF having TRP-69, PHE-40, ASP-350, LEU-73, PHE-390, ARG-393, LEU-391, LEU-100, ALA-99, SER-77, and PHE-32 amino acid residues participating in the interaction. Similarly, cyclopentaneundecanoic acid from Cassia alata demonstrated the best docked score (− 7.6 kcal/mol) with 2AJF having ASP-350, PHE-30, TRP-69, ARG-393, PHE-390, LEU-391, LEU-73, ALA-99, GLN-102, GLN-101, SER-77, and LEU-100 amino acid residues participating in the interaction. Of all the phytochemicals present in Phyllanthus amarus, o-Xylene revealed the best docked score (− 6.4 kcal/mol) with 2AJF. PRO-415, THR-414, ALA-413, THR-434, GLU-345, PHE-438, and HIS-540 amino acid residues participating in the interaction at the binding pocket of 2AJF. Cyclopentaneundecanoic acid from Vernonia amygdalina displayed the best docked score (− 7.7 kcal/mol) with 2AJF having PHE-69, PHE-40, PHE-32, LEU-73, SER-77, LEU-100, ALA-99, GLN-102, ASN-394, ARG-393, ASP-350, PHE-390, and LEU-391 amino acid residues participating in the interaction. Furthermore, cyclopentaneundecanoic acid from Anacardium occidentale demonstrated the best docked score (− 7.3 kcal/mol) with 2AJF having LEU-351, PHE-40, TRP-69, ASP-350, GLU-37, GLY-352, PHE-390, ARG-393, LEU-391, LEU-73, LEU-100, and ALA-99 amino acid residues participating in the interaction.

Fig. 13

Docking analysis and visualization of 2AJF binding with the best ligands with the highest docking score

Fig. 14

Binding-interaction analysis of 2AJF binding with the best ligands with the highest docking score

Table 13

Binding analysis of the best ligand with 2AJF (SARS coronavirus spike receptor-binding domain)

ID	Ligand	Amino acid residues involved in the interaction	Polar information
A	9,12-Octadecadienoic acid (Z,Z)-	ALA-348, SER-44, PHE-40, PHE-390, ASN-394, TRP-349, GLU-37, GLY-352, ASP-350, LEU-351, ARG-393	ASP-350 2.8 Å, ARG-393 3.5 Å
B	N-Cyclododecylacetamide	TRP-69, PHE-40, ASP-350, LEU-73, PHE-390, ARG-393, LEU-391, LEU-100, ALA-99, SER-77, PHE-32	ASP-350 2.4 Å
C	Cyclopentaneundecanoic acid	ASP-350, PHE-30, TRP-69, ARG-393, PHE-390, LEU-391, LEU-73, ALA-99, GLN-102, GLN-101, SER-77, LEU-100	GLN-101 4.6 Å ALA-99 2.4 Å LEU-100 2.3 Å
D	o-Xylene	PRO-415, THR-414, ALA-413, THR-434, GLU-345, PHE-438, HIS-540	No polar contacts
E	Cyclopentaneundecanoic acid	PHE-69, PHE-40, PHE-32, LEU-73, SER-77, LEU-100, ALA-99, GLN-102, ASN-394, ARG-393, ASP-350, PHE-390, LEU-391	No polar contacts
F	Cyclopentaneundecanoic acid	LEU-351, PHE-40, TRP-69, ASP-350, GLU-37, GLY-352, PHE-390, ARG-393, LEU-391, LEU-73, LEU-100, ALA-99	ASP-350 2.8 Å ARG-393 3.5 Å

.)]-

Molecular docking analysis of SARS-COV2 major protease (6LU7)

Figure 15, Fig. 16, and Table 14 present the molecular docking analysis and visualization of 6LU7 binding with the best ligands with the highest docking scores. Of all the examined phytocompounds from Azadirachta indica, 4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl) 3,5, dimethyl, 1H pyrrole-2-carboxylic acid ethyl ester displayed the highest docked score (− 7.6 kcal/mol) with the SARS-COV2 major protease (6LU7). MET-49, TYR-54, GLN-189, ARG-188, ASP-187, HIS-164, MET-165, GLU-166, HIS-163, LEU-141, SER-144, LYS-145, ASN-142, GLY-143, and CYS-145 amino acid residues participating in the interaction at the binding pocket of 6LU7. 2-Ethylacridine from Corchorus olitorius presented the highest affinity score (− 6.9 kcal/mol) with 6LU7 having ARG-105, ILE-106, GLN-110, OHE-294, ASP-153, ILE-152, ASN-151, and PHE-8 amino acid residues participating in the interaction. Equally, 6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2-methylsulfanyl ethyl ester from Cassia alata produced the greatest docked score (− 6.9 kcal/mol) with 6LU7 having PHE-140, LEU-141, HIS-172, GLU-166, MET-165, SER-144, ASN-142, GLY-143, CYS-145, HIS-163, HIS-164, GLN-189, HIS-41, THR-26, LEU-27, and MET-49 amino acid residues participating in the interaction. Out of all the phytocompounds present in Phyllanthus amarus, cyclododecylamine displayed the peak affinity score (− 5.2 kcal/mol) with 6LU7. PHE-294, GLN-110, ASN-151, THR-111, SER-158, LYS-102, and ASP-153 amino acid residues “participated” in the interaction at the binding pocket of 6LU7. N-Cyclododecylacetamide from Vernonia amygdalina exhibited the best docked score (− 6.0 kcal/mol) with 6LU7 having G;U-240, VAL-202, HIS-246, ILE-249, ILE-200, ASN-203, PRO-293, GLN-110, GLY-109, and PRO-108 amino acid residues participating in the interaction. Additionally, 1H-Indole, 5-methyl-2-phenyl- from Anacardium occidentale demonstrated the best docked score (− 7.2 kcal/mol) with 6LU7 having LEU-141, ASN-142, GLY-143, MET-165, HIS-164, CYS-145, HIS-41, GLN-189, TYR-54, ASP-187, ARG-188, and MET-49 amino acid residues participating in the interaction.

Fig. 15

Docking analysis and visualization of 6LU7 binding with the best ligands with the highest docking score

Fig. 16

Bind-interaction analysis of 6LU7 binding with the best ligands with the highest docking score

Table 14

Binding analysis of the best ligand with 6lu7 (COVID-19 main protease)

ID	S/N	Ligand	Amino acid residues involved in the interaction	Polar information
A	1	4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl) 3,5, dimethyl, 1H pyrrole-2-carboxylic acid ethyl ester	MET-49, TYR-54, GLN-189, ARG-188, ASP-187, HIS-164, MET-165, GLU-166, HIS-163 LEU-141, SER-144, LYS-145, ASN-142, GLY-143, CYS-145	GLY-143 2.9 Å HIS-163 3.4 Å SER-144 2.7 Å
B	2	2-Ethylacridine	ARG-105, ILE-106, GLN-110, OHE-294, ASP-153, ILE-152, ASN-151, PHE-8	No polar contacts
C	3	6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2-methylsulfanyl ethyl ester	PHE-140, LEU-141, HIS-172, GLU-166, MET-165, SER-144, ASN-142, GLY-143, CYS-145, HIS-163, HIS-164, GLN-189, HIS-41, THR-26, LEU-27, MET-49	No polar contacts
D	4	Cyclododecylamine	PHE-294, GLN-110, ASN-151, THR-111, SER-158, LYS-102, ASP-153	ASP-153 2.5 Å SER-158 2.0 Å
E	5	N-Cyclododecylacetamide	G;U-240, VAL-202, HIS-246, ILE-249, ILE-200, ASN-203, PRO-293, GLN-110, GLY-109 PRO-108	No polar contacts
F	6	1H-Indole, 5-methyl-2-phenyl-	LEU-141, ASN-142, GLY-143, MET-165, HIS-164, CYS-145, HIS-41, GLN-189, TYR-54, ASP-187, ARG-188, MET-49	No polar contacts

Molecular docking analysis of ADP ribose phosphatase of NSP3 from SARS CoV-2 (6VXS)

The computational analysis of 6VXS binding with the best ligand with the highest docking score is shown in Fig. 17, Fig. 18, and Table 15. Out of the investigated phytochemicals from Azadirachta indica, 4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl), 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester exhibited the best docked score (− 7.9 kcal/mol) with the ADP ribose phosphatase of NSP3 from SARS CoV-2 (6VXS). The amino acid residues taking part in the interaction at the binding pocket of 6VXS are LEU-160, PHE-156, VAL-155, ALA-154, GLY-130, ILE-131, PHE-132, SER-128, ALA-38, VAL-49, ALA-129, LEU-160, PRO-136, and PRO-125. 2-Ethylacridine from Corchorus olitorius displayed the best docked score (− 7.5 kcal/mol) with 6VXS having LEU-160, PHE-156, VAL-155, ALA-154, ASP-22, ILE-23, and LEU-126 amino acid residues participating in the interaction. Similarly, 6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2-methylsulfanyl ethyl ester from Cassia alata demonstrated the best docked score (− 5.5 kcal/mol) with 6VXS having PRO-125, LEU-126, ILE-23, ALA-165, VAL-49, ALA-154, ALA-21, ASP-22, ASP-157, LEU-160, GLY-130, and VAL-155 amino acid residues participating in the interaction. Of all the phytochemicals present in Phyllanthus amarus, cyclododecylamine revealed the best docked score (− 5.5 kcal/mol) with 2AJF. VAL-49, PHE-156, VAL-155, ALA-154, ALA-21, ILE-23, and ASP-22 amino acid residues participated in the interaction at the binding pocket of 6VXS. Cyclopentaneundecanoic acid from Vernonia amygdalina displayed the best docked score (− 6.8 kcal/mol) with 6VXS having LEU-160, VAL-155, GLY-130, ILE-23, VAL-49, VAL-125, ALA-129, ALA-154, LEU-126, PHE-156, and ALA-21 amino acid residues participating in the interaction. Furthermore, 1H-Indole, 5-methyl-2-phenyl- from Anacardium occidentale demonstrated the best docked score (− 7.4 kcal/mol) with 6VXS having ALA-154, LEU-126, ILE-23, VAL-49, and LEU-160 amino acid residues participating in the interaction.

Fig. 17

Docking analysis and visualization of 6VXS binding with the best ligands with the highest docking score

Fig. 18

Bind-interaction analysis of 6VXS binding with the best ligands with the highest docking score

Table 15

Binding analysis of the best ligand with 6VXS (ADP ribose phosphatase of NSP3 from SARS CoV-2)

ID	S/N	Ligand	Amino acid residues involved in the interaction	Polar information
A	1	4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl), 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester	LEU-160, PHE-156, VAL-155, ALA-154, GLY-130, ILE-131, PHE-132, SER-128, ALA-38, VAL-49, ALA-129, LEU-160, PRO-136, PRO-125	ALA-129 3.5 Å
B	2	2-Ethylacridine	LEU-160, PHE-156, VAL-155, ALA-154, ASP-22, ILE-23, LEU-126	PHE-156 3.5 Å
C	3	6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2-methylsulfanyl ethyl ester	PRO-125, LEU-126, ILE-23, ALA-165, VAL-49, ALA-154, ALA-21, ASP-22, ASP-157, LEU-160, GLY-130, VAL-155	VAL-155 3.2 Å
D	4	Cyclododecylamine	VAL-49, PHE-156, VAL-155, ALA-154, ALA-21, ILE-23, ASP-22	No polar contacts
E	5	Cyclopentaneundecanoic acid	LEU-160, VAL-155, GLY-130, ILE-23, VAL-49, VAL-125, ALA-129, ALA-154, LEU-126, PHE-156, ALA-21	ALA-21 2.8 Å
F	6	1H-Indole, 5-methyl-2-phenyl-	ALA-154, LEU-126, ILE-23, VAL-49, LEU-160	ALA-154 2.5 Å

Molecular docking analysis of SARS CoV-2 RNA-dependent RNA polymerase (7BTF)

Figure 19, Fig. 20, and Table 16 show the molecular docking analysis and visualization of 7BTF binding with the best ligand with the highest docking score. Of all the examined phytocompounds from Azadirachta indica, 1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane displayed the highest docked score (− 7.8 kcal/mol) with the SARS CoV-2 RNA-dependent RNA polymerase (7BTF). The participating amino acid residues in the interaction at the binding pocket of 7BTF are ASN-710, LYS-38, ASN-36, LYS-47, PHE-45, VAL-39, PHE-45, PHE-32, THR-203, ASP-205, ASP-33, ILE-34, and LYS-70. 2-Ethylacridine from Corchorus olitorius presented the highest affinity score (− 7.1 kcal/mol) with 6LU7 having LEU-368, ALA-372, PHE-365, LEU-369, PHE-503, TYR-512, LEU-511, and TRP-506 amino acid residues participating in the interaction. Equally, 6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2-methylsulfanyl ethyl ester from Cassia alata produced the greatest docked score (− 7.2 kcal/mol) with 7BTF having LYS-70, LYS-47, ASP-205, THR-203, ASN-36, LYS-38, ASN-710, VAL-39, ASP-33, ILE-34, PHE-32, and PHE-45 amino acid residues participating in the interaction. Out of all the phytocompounds present in Phyllanthus amarus, cyclododecylamine displayed the peak affinity score (− 6.0 kcal/mol) with 7BTF. The amino acid residues- ALA-372, TRP-506, LEU-511, PHE-365, LEU-368, LEU-369, TYR-512, and PHE-503 participated extensively in the interaction at the binding pocket of 7BTF. Carbamic acid [1-(hydroxymethyl)-2-phenylethyl]-1,1-dimethylethyl ester, (s)- from Vernonia amygdalina exhibited the best docked score (− 6.6 kcal/mol) with 7BTF having PHE-45, LEU-46, PHE-32, ILE-34, PHE-45, LYS-47, THR-48, ASN-49, and LYS-70 amino acid residues participating in the interaction. Additionally, 1H-Indole, 5-methyl-2-phenyl- from Anacardium occidentale demonstrated the best docked score (− 7.1 kcal/mol) with 7BTF having ASP-215, THR-203, ASN-206, ASP-205, ILE-34, PHE-32, PHE-45, LYS-47, THR-48, and LYS-70 amino acid residues participating in the interaction.

Fig. 19

Docking analysis and visualization of 7B binding with the best ligands with the highest docking score

Fig. 20

Bind-interaction analysis of 7B binding with the best ligands with the highest docking score

Table 16

Binding analysis of the best ligand with 7BTF (SARS CoV-2 RNA-dependent RNA polymerase)

ID	S/N	Ligand	Amino acid residues involved in the interaction	Polar information
A	1	1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane	ASN-710, LYS-38, ASN-36, LYS-47, PHE-45, VAL-39, PHE-45, PHE-32, THR-203, ASP-205, ASP-33, ILE-34, LYS-70	ASN-36 2.1 Å
B	2	2-Ethylacridine	LEU-368, ALA-372, PHE-365, LEU-369, PHE-503, TYR-512, LEU-511, TRP-506	No polar contacts
C	3	6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2-methylsulfanyl ethyl ester	LYS-70, LYS-47, ASP-205, THR-203, ASN-36, LYS-38, ASN-710, VAL-39, ASP-33, ILE-34, PHE-32, PHE-45	ASN-36 2.1 Å
D	4	Cyclododecylamine	ALA-372, TRP-506, LEU-511, PHE-365, LEU-368, LEU-369, TYR-512, PHE-503	No polar contacts
E	5	Carbamic acid, [1-(hydroxymethyl)-2-phenylethyl]-, 1,1-dimethylethyl ester, (s)-	PHE-45, LEU-46, PHE-32, ILE-34, PHE-45, LYS-47, THR-48, ASN-49, LYS-70	LEU-46 2.1 Å THR-48 2.3 Å
F	6	1H-Indole, 5-methyl-2-phenyl-	ASP-215, THR-203, ASN-206, ASP-205, ILE-34, PHE-32, PHE-45, LYS-47, THR-48, LYS-70	ASP-215 2.7 Å THR-203 2.6 Å ASN-206 2.1 Å, 2.3 Å, 2.6 Å

In silico toxicity and ADME of the phytochemicals with best docking score

Molecular properties of the phytochemicals with best docking score

Results in Table 17 showed the molecular properties of the phytochemicals with the best docking score. 6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2-methylsulfanyl ethyl ester was found to have the highest molecular weight of 374.364, followed by 4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl) 3,5, dimethyl, 1H pyrrole-2-carboxylic acid ethyl ester with 365.394. Similarly, 4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl) 3,5, dimethyl, 1H pyrrole-2-carboxylic acid ethyl ester and 2-Ethylacridine have the highest surface area of 151.006. Furthermore, 9,12-Octadecadienoic acid (Z,Z)- has the highest lipophilicity of 5.8845.

Table 17

Molecular properties of phytochemicals with best docking scores

Ligand	Molecular weight	Lipophilicity (Log P)	Number of rotatable bonds	Number of acceptors	Number of donors	Surface area
9,12-Octadecadienoic acid (Z,Z)-	280.452	5.8845	14	1	1	124.52
N-Cyclododecylacetamide	225.376	3.7958	1	1	1	100..189
Cyclopentaneundecanoic acid	254.414	5.1622	11	1	1	112.163
o-Xylene	106.166	2.30344	0	0	0	50.161
4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl) 3,5, dimethyl, 1H pyrrole-2-carboxylic acid ethyl ester	365.394	2.62302	3	6	2	151.006
2-Ethylacridine	355.394	2.62302	3	6	2	151.006
6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester	374.364	2.3295	5	4	2	146.541
Cyclododecylamine	163.339	3.6184	0	1	1	83.088
1H-Indole, 5-methyl-2-phenyl-	207.275	4.14332	1	0	1	94.744
1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane	296.41	4.6911	3	2	0	132.629
Carbamic acid, [1-(hydroxymethyl)-2-phenylethyl]-, 1,1-dimethylethyl ester, (s)-	251.326	2.1147	4	3	2	107..970

Predicted absorption properties of the phytochemicals with best docking score

The predicted absorption properties of the phytochemicals were reported in Table 18. The result showed that 9,12-Octadecadienoic acid (Z,Z)- has the highest water solubility value of − 5.862 while Cyclododecylamine has the lowest valve of − 2.651. O-Xylene has the highest permeability value of 1.574, but 6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2-methylsulfanyl ethyl ester has the least permeability valve of 0.927. Likewise, all the phytochemicals can be readily absorbed by the intestinal cells, with 2-Ethylacridine having the highest intestinal absorption of 98.202%. All the phytochemicals are substrate of P-glycoprotein expect 9,12-Octadecadienoic acid (Z,Z)-, cyclopentaneundecanoic acid, and o-Xylene. None of the phytochemicals is neither inhibitor of P-glycoprotein-I nor P-glycoprotein-II.

Table 18

Predicted absorption properties of phytochemicals with best docking scores

Ligand	Water solubility (log mol/L)	Caco2 permeability (log Papp in 10–6 cm/s)	Intestinal absorption (% absorbed)	Skin permeability (log Kp)	P-glycoprotein substrate	P-glycoprotein I inhibitor	P-glycoprotein II inhibitor
9,12-Octadecadienoic acid (Z,Z)-	− 5.862	1.57	92.329	− 2.723	No	No	No
N-Cyclododecylacetamide	− 3.487	1.477	92.574	− 2.178	Yes	No	No
Cyclopentaneundecanoic acid	− 5.364	1.566	92.079	− 2.716	No	No	No
o-Xylene	− 2.552	1.574	96.713	− 1.236	No	No	No
4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl) 3,5, dimethyl, 1H pyrrole-2-carboxylic acid ethyl ester	− 3.763	0.964	88.393	− 3.659	Yes	No	No
2-Ethylacridine	-5.037	1.355	98.202	-2.246	YES	NO	NO
6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester	-4.159	0.927	89.551	-3.136	YES	NO	NO
Cyclododecylamine	− 2.651	1.341	92.472	− 2.402	Yes	No	No
1H-Indole, 5-methyl-2-phenyl-	− 5.006	1.541	93.388	− 2.507	Yes	No	No

Predicted in vivo distribution, clearance, and cytochrome P450 promiscuity of the phytochemicals with best docking score

Table 19 shows the predicted in vivo distribution of the phytochemicals. All the phytochemicals tested have relatively low steady-state volume of distribution. Similarly, the predicted result demonstrated that Cyclododecylamine has the highest unbound fraction in the human blood. All the phytochemicals have relatively low blood–brain barrier and CNS permeability values.

Table 19

Predicted in vivo distribution and excretion properties of phytochemicals with best docking scores

Ligand	VDss (human)	Fraction unbound (human)	BBB permeability	CNS permeability	Total Clearance	Renal OCT2 substrate
9,12-Octadecadienoic acid (Z,Z)-	− 0.587	0.054	− 0.142	− 1.6	1.936	No
N-Cyclododecylacetamide	0.277	0.49	0.494	− 3.388	1.426	No
Cyclopentaneundecanoic acid	− 0.568	0.084	− 0.034	− 1.567	1.465	No
o-Xylene	0.325	0.362	0.409	− 1.677	0.269	No
4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl) 3,5, dimethyl, 1H pyrrole-2-carboxylic acid ethyl ester	0.119	0.324	− 0.113	− 3.032	0.996	No
2-Ethylacridine	0.449	0.197	0.526	− 1.372	0.829	No
6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester	− 0.279	0.14	− 0.332	− 2.922	0.141	No
Cyclododecylamine	0.682	0.599	0.397	− 3.167	0.707	No
1H-Indole, 5-methyl-2-phenyl-	0.284	0.106	0.571	− 1.384	0.417	No
1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane	− 5463	1.791	98.046	− 2.41	0.137	No
Carbamic acid, [1-(hydroxymethyl)-2-phenylethyl]-, 1,1-dimethylethyl ester, (s)-	− 2.895	1.284	92.921	− 3.189	0.481	No

The predicted clearance of each of the phytochemicals showed that 9,12-Octadecadienoic acid (Z,Z)- has the highest total clearance rate of 1.936, while 1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane has the least clearance rate of − 0.137. None of the phytochemicals is substrate of renal organic cation transporter.

Table 20 displays the predicted human cytochrome P450 promiscuity of the phytochemicals. All the phytocompounds were neither substrate nor inhibitor of CYP2D6 expect 2-Ethylacridine which could be inhibitor of CYP2D6. Similarly, none of the phytochemicals expect cyclopentaneundecanoic acid is inhibitor of CYP3A4. Cyclododecylamine and 4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl) 3,5, dimethyl, 1H pyrrole-2-carboxylic acid ethyl ester were neither substrate nor inhibitor of any of the cytochrome P450 tested in this study.

Table 20

Predicted cytochrome P450 promiscuity of phytochemicals with best docking scores

Ligand	CYP2D6 substrate	CYP3A4 substrate	CYP1A2 inhibitor	CYP2C19 inhibitor	CYP2C9 inhibitor	CYP2D6 inhibitor	CYP3A4 inhibitor
9,12-Octadecadienoic acid (Z,Z)-	No	Yes	Yes	No	No	No	No
N-Cyclododecylacetamide	No	No	No	No	No	No	No
Cyclopentaneundecanoic acid	No	No	Yes	No	No	No	Yes
o-Xylene	No	No	No	No	No	No	No
4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl) 3,5, dimethyl, 1H pyrrole-2-carboxylic acid ethyl ester	No	No	No	No	No	No	No
2-Ethylacridine	No	YesS	Yes	Yes	Yes	Yes	No
6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester	No	YesS	No	No	No	No	No
Cyclododecylamine	No	No	No	No	No	No	No
1H-Indole, 5-methyl-2-phenyl-	No	Yes	Yes	Yes	Yes	No	No
1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane	No	Yes	Yes	Yes	No	No	No
Carbamic acid, [1-(hydroxymethyl)-2-phenylethyl]-, 1,1-dimethylethyl ester, (s)-	No	No	Yes	No	No	No	No

Predicted toxicological profile of the phytochemicals with best docking score

Table 21 displays the predicted toxicological profile of the phytochemicals with best docking scores with the pathogenic proteins. All the phytochemicals have no mutagenic potentials against bacteria (AMES toxicity) except 2-Ethylacridine and 1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane could be toxic to bacteria. None of the phytochemicals has adverse effects on the hepatic cells expect 9,12-Octadecadienoic acid (Z,Z)-; 4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl) 3,5, dimethyl, 1H pyrrole-2-carboxylic acid ethyl ester; and 6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2-methylsulfanyl ethyl ester. The phytochemicals are not inhibitors of human ether-a-go-go-related gene (hERG) hERG I and hERG II except 2-Ethylacridine and 6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2-methylsulfanyl ethyl ester which may inhibit hERG II. All the phytochemicals have relatively low maximum recommended tolerated dose values.

Table 21

In silico toxicological properties of phytochemicals with best docking scores

Ligand	Max. tolerated dose (human)	Oral rat acute toxicity (LD50)	Oral rat chronic toxicity (LOAEL)	T.Pyriformis toxicity	Minnow toxicity	AMES toxicity	hERG I inhibitor	hERG II inhibitor	Hepatotoxicity	Skin Sensitisation
9,12-Octadecadienoic acid (Z,Z)-	− 0.827	1.429	3.187	0.701	− 1.31	No	No	No	Yes	Yes
N-Cyclododecylacetamide	0.546	2.236	0.956	0.892	1.754	No	No	No	No	Yes
Cyclopentaneundecanoic acid	− 0.762	1.559	3.027	0.812	− 0.855	No	No	No	No	Yes
o-Xylene	0.921	1.841	2.169	− 0.022	1.31	No	No	No	No	No
4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl) 3,5, dimethyl, 1H pyrrole-2-carboxylic acid ethyl ester	− 0.35	2.548	0.34	0.417	1.616	No	No	No	Yes	No
2-Ethylacridine	− 0.255	1.739	1.146	1.188	− 0.7	Yes	No	Yes	No	No
6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester		2.712	0.99	1.052	1,393	No	No	Yes	Yes	No
Cyclododecylamine	0.611	2,258	1.166	0.51	1.838	No	No	No	No	Yes
1H-Indole, 5-methyl-2-phenyl-	0.147	1.904	1.002	1.274	0.554	No	No	No	No	No
1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane	0.149	2.468	2.065	1.151	− 0.314	Yes	No	No	No	No
Carbamic acid, [1-(hydroxymethyl)-2-phenylethyl]-, 1,1-dimethylethyl ester, (s)-	0.732	2.024	1.767	0.904	1.183	No	No	No	No	No

Discussion

SARS-CoV-2 has affected more than 212 million people with over 4.43 million fatalities globally, and the genome of this virus is associated with diverse mutation; hence, recognizing specific inherent proteins of this virus by small molecule drugs is a prime target in combatting its virulence (Kangarshahi et al. 2021; Patel et al. 2021). These proteins are of both structural (four) and non-structural (sixteen) functionality comprising approximately 7096 amino acid residues (Naqvi et al. 2020; Kumar et al. 2021). Hence, making multi-viral protein-targeting molecules suitable as potential anti-coronavirus drug candidates (Wu et al. 2020).

Oxidative stress, redox imbalance, cell death, inflammation, cytokine production, and other pathophysiological processes have been implicated in the pathogenesis of respiratory viral infections including severe acute respiratory syndrome coronavirus (SARSCoV) (Oladele et al. 2020a, b, c, d). Weakening antioxidant protective mechanisms and excessive secretion of reactive oxygen species (ROS) are vital for viral replication and the consequent virus-linked pathological conditions (Khomich et al. 2018). In this study, we reported the cytoprotective and antioxidative properties of six tropical plants used traditionally to prevent and treat COVID-19 and its associated clinical symptoms.

Several antioxidant assays were employed in this study to establish the antioxidant potentials of the aqueous extracts of the selected tropical plants. As shown in the results, all the extracts demonstrated substantial free radical scavenging and antioxidants activities. This indicates that these extracts serve as reservoirs of vital and medicinal phytochemicals such as phenols, flavonoids, tannins, and so on whose therapeutic efficacies have been scientifically established. These findings were corroborated by the GCMS analysis of the extracts revealing the phytochemicals present in them.

Scientific evidences have reported that activation of the oxidative stress machinery is vital in the initiation of severe lung injury in SARS-CoV-infected patients which associated with expression of transcription factors, including NF-kB, leading to an aggravated proinflammatory host response (Smith et al. 2012; Lin et al. 2006). Abrogation of this initiation process by phytochemicals present in extracts could provide health benefits and potent therapeutic solution to COVID-19 pandemic. Polyphenols and flavonoids have been reported in an in silico study to mitigate pathogenesis of COVID-19 (Oladele et al. 2021a, b).

It is well established that there exists link between oxidative stress and inflammation (Sies 2015). Activation of NF-kB with consequent excessive secretion proinflammatory cytokines is considered a crucial mediator in SARS-CoV pathophysiology (Smith et al. 2012; Padhan et al. 2008). In this study, the in vitro anti-inflammatory property of the extracts was assessed by evaluating their nitric oxide inhibitory effect. As depicted in the results, all the extracts exhibited significant nitric oxide inhibitory effect confirming their anti-inflammatory potentials. Nitric oxide is a mediator of nitrosative stress and also an inflammatory biomarker that has been implicated in pathogenesis of many diseases. Similarly, nitric oxide is mainly synthesized via inducible nitric oxide synthase (iNOS) under inflammatory conditions.

As shown in this present study, all the extracts contain phytochemicals that have inhibitory effect against the ADP ribose phosphatase. The macrodomain of the ADP ribose phosphatase has been documented to significantly contributes to the alteration of the viral-induced immune response of the host and enhance viral RNA replication owing to induced nuclear translocation of host type 1 interferon (INF-1) regulatory factor 3 (IRF3), an important innate immunity mediator. This property of seizing the host immune system makes this protein a unique drug target (Fehr et al. 2018; Michalska et al. 2020; Patel et al 2021). The in silico inhibition of this protein by the phytochemicals present in these extracts is indicative of their immune enhancing activity, thus playing vital role in mitigating the pathobiology of COVID-19.

Mainly associated with viral RNA replication and transcription, the RNA-dependent RNA polymerase (RdRp) in conjunction with other structural proteins such as Nsp 7 and Nsp 8 exhibits profound polymerase activity, making this enzyme a key target of most antiviral agents (Kirchdoerfer and Ward 2019; Jiang et al. 2021; Malone et al. 2022). In this study, phytochemicals present in these extracts remarkably inhibited RNA-dependent RNA polymerase as showed in the computational study, supporting the antiviral activity of these phytochemicals.

The result of this study also demonstrated that the phytochemicals contained in the aqueous extracts of the tropical plants markedly inhibited the SARS-CoV-2 main protease (Mpro). Mpro is a critical highly conserved protein engaged in the replication and maturation processes of SARS-CoV-2. It comprises of chymotrypsin and picornavirus 3 C protease-like catalytic domains. This protein is emerging as a significant antiviral target because of its role in proteolytic processing of viral polyproteins (Joshi et al. 2021; Abdul Amin et al. 2021).

Nsp9 and primase were also inhibited by the phytochemicals using computational approach. Nsp9, a 113 amino acid dimeric protein primarily functions in binding single stranded nucleic acids (DNA and RNA) during viral replication and its impairment, yields the synthesis of defective RNAs in the virus (Kangarshahi et al. 2021). Unlike other viral proteins/enzymes, the primase is vastly associated with de novo initiation of nucleic acids making it one of key enzymes driving the infectivity of SARS-CoV-2 (Konkolova et al. 2020). All these pathogenic proteins of COVID-19 were inhibited by the phytochemicals in the plant extracts suggesting them as potential anti-COVID-19 drug candidates.

The results of the solubility, pharmacodynamics, pharmacokinetics, and toxicological profiles of the phytochemicals were investigated as a systemic virtual screening of drugs and potential drugs. This is done as alternative to in vivo examinations which are essential complements in drug discovery. The Lipinski’s rule is a major criterion to evaluate drug likeliness and to determine if a compound with a particular pharmacological and biological action has physical and chemical properties that could favour its activities in human. The molecular properties of the compounds based on the computed partition coefficient (log P) showed that the phytochemicals have relatively good lipophilicity as the logP values were less than 5 (Lipinski et al. 1997; Hughes et al. 2008). All the tested phytochemicals could be maintained in the system at appropriate concentrations.

All the phytochemicals except 9,12-Octadecadienoic acid (Z,Z)-, cyclopentaneundecanoic acid, and o-Xylene were predicted to be substrates of P-glycoprotein, a member of the ATP-binding cassette transporter and an efflux membrane transporter found chiefly in epithelial cells. Conversely, none of the phytochemicals is predicted as P-glycoprotein inhibitors. This suggested that they don’t disrupt the normal physiological activities of P-glycoprotein including restricting the active uptake and the distribution of drugs (Srivalli and Lakshmi 2012).

Cytochrome P450 is a group of enzymes that perform crucial functions in drug metabolism. They play a major role in the activation of drugs and also in the toxicity effects of the drugs. None of the phytochemicals expect cyclopentaneundecanoic acid is inhibitor of CYP3A4. Also, all the phytocompounds were neither substrate nor inhibitor of CYP2D6 expect 2-Ethylacridine which could be inhibitor of CYP2D6. The lipophilicity of the drug appears to correlate negatively to metabolism-related toxicity. Furthermore, none of the phytochemicals were a substrate of renal organic cation transporter; this implies that they are possibly cleared through other available routes including bile, sweat, and so on. Furthermore, the phytochemical displayed substantial clearance results. Drug clearance is related to bioavailability and is crucial for determining dosing rates to achieve steady-state concentrations.

Acute and chronic toxicity were also carried out on the phytochemicals to determine the safety of the compounds when administered. Exposure to low-moderate doses/concentrations of xenobiotics over long period of time is of significant concern in many treatment strategies or interventions. Chronic studies are designed to identify the lowest dose of a compound that can result in adverse effects (LOAEL), and the highest dose at which no adverse effects are observed (NOAEL). The toxicological assessment of the phytochemicals revealed that all the phytochemicals are not hepatoxic expect 9,12-Octadecadienoic acid (Z,Z)-, 4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl esteryl) 3,5, dimethyl, 1H pyrrole-2-carboxylic acid ethyl ester, and 6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2-methylsulfanyl ethyl ester. Similarly, only 1,3,3-Trimethyl-1-(4′-methoxyphenyl)-6-methoxyindane and 2-Ethylacridine are bacterial mutagenic potential drugs using the AMES toxicity examination. However, all the compounds showed high level of toxicity to Tetrahymena pyriformis toxicity test. None of the phytochemicals is an inhibitor to hERG I, but 2-Ethylacridine and 6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrim idine-5-carboxylic acid 2-methylsulfanyl-ethyl ester 2-methylsulfanyl ethyl ester may be inhibitors to hERG II. Inhibition of the hERG potassium channel could result in delayed ventricular repolarisation leading to a severe disturbance in the normal cardiac rhythm and disrupt hepatic functions (Oso et al. 2019; Oladele et al. 2021a, b).

Conclusion

Put together, the data from this study demonstrated that the phytochemicals of the selected tropical medicinal plants displayed substantial binding affinity to the binding pockets of four main pathogenic proteins of Coronavirus-2 indicating these phytochemicals as putative inhibitors of Coronavirus-2. The reaction between these phytocompounds and proteins of Coronavirus-2 could alter the pathophysiology of COVID-19, thus mitigating its pathogenic reactions/activities. This study reported the in silico inhibitory activity of phytochemicals against four pathogenic proteins of Coronavirus-2. However, in vitro and in vivo studies are important to potentiate these findings. Other drug techniques or models are vital to elucidate their compatibility and usage of the phytochemicals as adjuvants in vaccine development against the highly contagious COVID-19 infection.