Molecular docking study of seventy-six phytomolecules from sixteen aromatics medicinal plants as promising inhibitors of five non-structural proteins of SARS-CoV-2

Since the identification of COVID-19 in China in December 2019, scientists and researchers have been continuously discovering and proposing drugs for this disease. Many efforts have been made to examine medicinal plants known for their benefits in treating infectious diseases and for their actions in boosting of the immune system. Repurposing of FDA-approved antiviral drugs has also been advanced. However, no effective antiviral drug specific to COVID-19 is currently available. To contribute in the search for drugs against this disease, the present study aims to identify secondary metabolites (or phytomolecules) possessing an inhibitory effect on the replication of SARS-CoV-2, the etiological agent of COVID-19. 76 secondary metabolites from 16 aromatics medicinal plants from Madagascar were uploaded to the PubChem server. Then, they were docked with 5 non-structural proteins (nsps) of SARS-CoV-2, including the main protease, the papain-type protease, the RNA-dependent RNA polymerase, the helicase and the 2'-O-methyltransferase, using the Autodock Vina program integrated in the PYRIX 0.8 software. The results show that 5 secondary metabolites of Cinnamosma fragrans (Capsicodendrin, Ugandensolide, Cinnamolide, Tocotrienol and Pereniporin B) have good affinity with the 5 nsps of SARS-CoV-2 and can inhibit its functions in viral replication. Therefore, these phytomolecules could be used in the development of antiviral drugs against SARS-CoV-2 and COVID-19. Nevertheless, further in vitro and in vivo studies should be performed to valorize these results obtained by the in silico method.


Introduction
At the end of 2019, a new disease named COVID-19 and caused by a new coronavirus, known as Severe Acute Respiratory Syndrome Coronavirus-2 or SARS-CoV-2 has been reported in China [1].This disease has quickly spread throughout the world and is now causing a global pandemic worldwide.In December 2021, more than 9.49 million deaths have been reported worldwide [2].However, this number has continued to increase due to the emergence of new variants of SARS-CoV-2 such as Omicron [3].Faced with this situation, many pharmaceutical companies are trying to develop vaccines or drugs that will control the situation.Unfortunately, no pharmaceutical product has been approved as safe, effective and specific for the treatment and prevention of COVID-19.Only precautionary measures such as border surveillance, practicing self-hygiene, social distancing and wearing personal protective equipment are being practiced to prevent the spread of the disease.
In Madagascar and in other countries of the world, most of peoples have also used medicinal plants such as Artemisia annua, Eucalyptus globulus, Allium sativum, Zingiber officinalis and many others to fortify the medicines offered by the doctors [4][5][6].Although the pharmacological importance of these plants in other infectious diseases is well documented, no conclusive experimental results have been found to prove their effectiveness in the treatment of COVID-19.
Currently, advances in bioinformatics have made it possible to screen bioactive compounds in plants and to evaluate their pharmacological properties [7].In order to contribute to the search for drugs against COVID-19, this study aims to identify phytomolecules with an inhibitory effect on SARS-CoV-2 replication in sixteen aromatic medicinal plants from Madagascar.The results of these studies can be used in other in vitro and/or in vivo studies to develop an effective drug against this disease.

Selection and preparation of ligands
In this study, we selected seventy-six secondary metabolites (phytomolecules) from six-teen aromatic medicinal plants from Madagascar.The information about these phytomolecules and their percentages in the selected plants are summarized in Supplementary Table 1.The structure data file (.sdf) in two-dimensional (2D) or three-dimensional (3D) formats and the canonical SMILES files of these 76 selected phytomolecules were downloaded to the PubChem database (www.pubchem.ncbi.nlm.nih.gov ).They are used in molecular docking studies.

Selection and preparation of receptors
We selected five non-structural proteins (nsps) from SARS-CoV-2, including main protease (Mpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), helicase and 2'-O-methyltransferase (2'-O-Mtase).These proteins are selected for their involvement in virus replication and in the host immune response [8,9].Their 3D structures were retrieved from the RCSB PDB database (http://www.rcsb.org), using the identification numbers shown in Table 1.Then, the co-crystallized ligands and water molecules in those structures were removed, using Discovery Studio Visualizer version 2017 or D.S v2017 software (http://accelrys.com/products/collaborativescience/biovia-discovery ) [10].Afterwards, the structures without ligands were minimized in the UCSF CHIMERA software, using the Amber force field ff94 [11].Finally, the minimized structures are saved in .pdbformat in the same software.

Determination of receptor active site residues
The amino acid (aa) residues composing the active site of the targeted nsps were predicted using COACH-D server (http://yanglab.nankai.edu.cn/COACH-D/ ).This server is the improuved version of the COACH server and uses five individual methods to predict protein-ligand binding sites [17].In the prediction, we submitted in the server the previously prepared 3D structures of nsps.Then, computations were performed by the server and the best predicted results were proposed.Among the proposed results, we selected only the residues appearing in the first rank (whose confidence scores are also high).The positions of these residues in the 3D structure of the nsps are visualized using the D.S v2017 software.

Molecular docking
Molecular docking was performed using the PYRX 0.8 software (http://pyrx.sourceforge.net/downloads) [18].Before docking, the 3D structures of the receptors (nsps) were imported into the PYRX 0.8 software in .pdbformat.Then, the 3D structures of the ligands (phytomolecules) were uploaded in .sdfformat and were minimized using Open Babel, a tool integrated in the same software [19].Afterwards, the receptor and ligand files were converted to .pdbqtformats via the Autodock4 [20].During docking, all ligands are considered as flexible and all receptors are considered as rigid.
The grid box parameters are configured using the X, Y, Z coordinates summarized in Table 2.All docking calculations are performed with the program AutoDock Vina [21].After docking, the complexes with the lowest binding energy (kcal/mol) were selected and the interaction modes of phytomolecules with nsps are visualized in D.S v2017.

Selected ligands
Among the seventy-six phytomolecules selected, fifty-five phytomolecules are classed in the terpenoid family.They include thirty-three monoterpenes and twenty-two sesquiterpenes (Table 3).The remaining twenty-one phytomolecules are organo-sulfur, organo-oxygen and aromatic compounds.These results indicate that most of the selected phytomolecules are terpenoids.

Target proteins and active site residues
In this study, we targeted five nsps of SARS-CoV-2 including Mpro, PLpro, RdRp, Helicase and 2'-O-MTase.Their 3D structures are retrieved from the RCSB PDB database and the amino acid residues that form their active sites are predicted using COACH-D server.The following paragraphs describe the results obtained after the 3D structure analysis and the prediction of the active site residues of these targeted proteins.

Proteases
Mpro is constituted of 306 amino acid residues (aa), which are divided into three domains including DI, DII, DIII and a long loop.The active site of this enzyme is located in the center of the groove formed by the domains DI and DII (Figure 1A).COACH-D server predicted the following residues Thr 25 , His  As for PLpro, it is composed of 316 aa that are divided into five sub-domains: ubiquitin-like (UBL), thumbs, fingers and palm.Its active site is located at the interface of the thumb and palm sub-domains (Figure 1B).The residues Asp 164 , Val 165 , Arg 166 , Ala 249 , Gln 250 , Gly 266 , Gln 269 , Cys 270 , Gly 271 , His 275 , Val 303 were predicted by the COACH-D server as the active site residues of this enzyme.Thus, the three residues forming the triad site Cys 111 , His 272 and Asp 286 of this enzyme were not predicted.

RdRp
The RdRp enzyme is composed of 1085aa which is divided into three subunits including nsp12 (chain A, 859aa), nsp7 (chain C, 70aa) and nsp8 (chains B and D, 156aa).Structurally, nsp12 resembles a right hand, comprising the beta hairpins, NIRAN, Interface, finger, palm and thumb sub-domains.The nsp7 and nsp8 subunits bind to the thumb and an additional copy of nsp8 binds to the fingers sub-domain.The active site is located in the palm sub-domain (Figure 2).Upon prediction, COACH-D defined the following residues as active site residues of RdRp: Pro 809 , Glu 811 , Phe 812 , Cys 813 , Ser 814 , His 816 , Thr 817 , Met 818 , Leu 819 , Val 820 , Lys 821 , Gln 822 , Gly 823 , Asp 824 .However, visualization of the positions of these residues at the 3D structure of the enzyme in D.S v2017 excluded the amino acids His 816 , Thr 817 , Met 818 , Leu 819 , Val 820 , Lys 821 , Gln 822 , Gly 823 , Asp 824 among the active site residues (Figure 2).

Helicase and 2'-O-MTase
The helicase consists of 593aa that correspond to five domains including the N-terminal zinc-binding domain (ZBD), the stalk domain, the 1B domain, the 1A domain, and the 2A domain.The last three domains 1A, 1B, and 2A formed two sites, including the DNA binding site and the ATP hydrolysis site (Figure 3A).Furthermore, prediction of the residues of the helicase active site by the COACH-D server revealed the following amino acids: Leu 256 , Ser 278 , Leu 280 , Gln 281 , Gly 282 , Pro 283 , Pro 284 , Gly 285 , Asp 315 , Thr 367 , Tyr 396 , Pro 434 , Asp 435 , Thr 530 , Thr 532 and Asn 559 .Furthermore, visualization of these amino acids in the 3D structure of the helicase showed that the first thirteen residues were located in the ATP hydrolysis site, whereas the last three residues were located in the DNA binding site (Figure 3A).
The 2'-O-MTase or nsp16 is crystallized with nsp10.This complex is formed by 438aa which is grouped in two chains: the B chain for nsp10 (139aa) and the A chain for nsp16 (299aa).The nsp16 contains a tetrad catalytic site formed by Lys 46 , Asp 130 , Lys 170 and Glu 203 and two substrate binding pockets including the RNA binding site and the Sadenosylmethionine or SAM binding site (Figure 3B).A total of eighteen amino acids were predicted by COACH-D server to be residues of the 2'-O-MTase active site.A visualization of the position of these residues in the 3D structure of this enzyme via D. S v2017 revealed that the residues Asn 43 , Gly 71 , Ala 72 , Gly 73 , Ser 74 , Ala 79 , Pro 80 , Gly 81 , Asp 99 , Leu 100 , Asn 101 , Gly 113 , Asp 114 , Cys 115 , Asp 130 , Met 131 and Tyr 132 are located in the RNA binding site, whereas Lys 170 is localized in the SAM (Figure 3B).Indeed, we predicted only the two residues Asp 130 , Lys 170 among the four residues of the tetrad catalytic site Lys 46 -Asp 130 -Lys 170 -Glu 203 of the 2'-O-MTase enzyme.Molecular docking was used to simulate the interactions of the seventy-six selected phytomolecules with the five target nsps.In terms of energy, the results obtained indicated that only five phytomolecules out of the seventy-six tested showed strong interactions with the five target proteins (Table 4).Surprisingly, these five phytomolecules are the drimane sesquiterpenes of Cinammosma fragrans.The others phytomolecules showed lower interaction energies than these five selected phytomolecules (Supplementary table 2).

The modes of interaction of phytomolecules with target proteins
The interaction modes of these five selected phytomolecules with Mpro, PLpro, RdRp, Helicase and 2'-O-MTase were visualized in D.S v2017.The following paragraphs summarize the results obtained.

Mpro
These five phytomolecules are also well anchored in the active site of Mpro (Figure 4).Indeed, capsicodendrin formed five hydrogen bonds with Thr 26 , Gln 142 , Gly 143 , Ser 144 and Cys 145 and three other hydrophobic bonds with Met 49 , Cys 145 and His 163 (Figure 4A).In addition, Ugandensolide formed two hydrogen bonds with Ser 144 and Cys 145 and two hydrophobic bonds with Cys 145 and His 163 (Figure 4B).In addition, Cinnamolide formed two hydrogen bonds with Leu 141 , Cys 145 and three hydrophobic bonds with Cys 145 /His 163 (Figure 4C).Also, one hydrogen bond with Thr 190 and three hydrophobic bonds with Met 49 , Cys 145 and Met 165 were observed between Tocotrienol and Mpro (Figure 4D).Finally, the interactions of Pereniporin B with Mpro were stabilized only by four hydrogen bonds with Ser 144 , Gly1 43 and Cys 145 (Figure 4E).In summary, four phytomolecules (except Tocotrienol) made three or more interactions with the amino acids responsible for protease activity of this enzyme.We suggest that these interactions are sufficient to inhibit the activity of this enzyme.

PLpro
The five selected phytomolecules are also well anchored in the active site of PLpro (Figure 5).Capsicodendrin established three hydrogen bonds with Leu 162 , Arg 166 and Tyr 264 and three hydrophobic bonds with Pro 147 , Pro 148 and Tyr 264 (Figure 5A).In addition, two hydrogen bonds with Arg 166 , Tyr 264 and three additional hydrophobic bonds with Pro 147 , Pro 148 and Tyr 264 were found between Ugandensolide and PLpro (Figure 5B).However, only four hydrogen bonds (Pro 147 , Pro 148 and Tyr 264 ) were observed in the interaction between Cinnamolide and PLpro (Figure 5C).On the other hand, three hydrogen bonds and three hydrophobic bonds were formed between Tocotrienol and PLpro, and this involves seven residues including: Pro 148 , Leu 162 , Asp 164 , Arg 166 , Pro 248 , Tyr 264 and Tyr 273 (Figure 5D).Finally, one hydrogen bond via Tyr 273 and three hydrophobic bonds via Pro 148 and Tyr 264 contributed to the stabilization of the interaction between Pereniporin B and PLpro (Figure 5E).In these results, we noticed that all phytomolecules interacted with the residues of the PLpro active site but none of the residues of the catalytic triad Cys 111 , His 275 and Asp 286 of this enzyme are involved in the interactions.This leads us to suggest that the 5 selected phytomolecules are non competitive inhibitors of the PLpro enzyme.

RdRp
Hydrogen and hydrophobic interactions involved the amino acids Trp 800 , His 810 , Glu 811 , Ser 814 and Lys 798 of the RdRp active site with Capsicodendrin (Figure 6A).Similarly, four hydrogen bonds with Trp 617 , Asp 760 , Asp 761 , Trp 800 and a hydrophobic bond with Lys 798 were found between Ugandensolide and RdRp (Figure 6D).In addition, hydrophobic interactions were observed between the amino acids Trp 800 and Lys 798 of the RdRp active site and Cinnamolide.Furthermore, Tocotrienol created one hydrogen bond with Trp 800 , and three hydrophobic bonds with Trp 800 , Lys 798 and Glu 811 (Figure 6D).Finally, the interaction of Pereniporin B with RdRp was only stabilized by Van Der Waals interactions (Figure 6E).These results indicate that only Ugandensolide interacted with two residues of the triadic 759 Ser-Asp-Asp 761 site of RdRp.Therefore, this phytomolecule should be a competitive inhibitor of this enzyme.The other phytomolecules such as Capsicodendrin, Cinnamolide, Tocotrienol and Pereniporin B interacted only with the other residues of the active site.They can therefore be described as non competitive inhibitors of the RdRp enzyme.Therefore, their inhibitory capacities depend on their binding energies to the enzyme.The amino acids Gly 285 , Lys 288 , Arg 443 , and Ala 316 in the active site of nsp13 are involved in the formation of three hydrogen bonds and three hydrophobic bonds with Capsicodendrin (Figure 7A).In addition, four hydrogen bonds and two hydrophobic bonds with Thr 286 , Gly 287 , Lys 288 , Arg 443 and Lys 288 and Ala 316 were found between Ugandensolide and helicase (Figure 7B).Furthermore, a hydrogen bond and an additional hydrophobic bond are found between Lys 285 and Ala 316 of the helicase and Cinnamolide (Figure 7C).We also found that Tocotrienol formed two hydrophobic bonds and one hydrophobic bond with Lys 288 and Ala 316 of the helicase (Figure 7D).Finally, pereniporin B formed a stable interaction with the helicase by forming six hydrogen bonds with Gly 285 , Thr 286 , Lys 288 , Ser 289 , Gly 538 and three hydrophobic bonds with Ala 316 (Figure 7E).All these residues that interact with phytomolecules are located in the ATP hydrolysis site of the helicase (Figure 3A).Thus, we conclude that the five phytomolecules selected in this study have the ability to inhibit the function of this enzyme by intervening at the ATP hydrolysis site.The interaction of Capsicodendrin with nsp16 involved four hydrogen bonds with Lys 46 , Gly 71 , Asn 101 , Asp 133 and three hydrophobic bonds with Leu 100 , Tyr 132 , Pro 134 (Figure 8A).In addition, Ugandensolide formed three hydrogen bonds with Asn 43 , Asn 101 and Asp 99 and two hydrophobic bonds with Tyr 132 , Pro 134 from nsp16 (Figure 8B).Concerning Cinnamolide, two hydrogen bonds and ten hydrophobic bonds engaged the amino acids Leu 100 , Cys 115 and Leu 100 , Cys 115 , Met 131 , Phe 149 for its interaction with nsp16 (Figure 8C).Furthermore, one hydrogen bond with Lys 170 and seven hydrophobic bonds with Leu 100 , Cys 115 , Met 131 , Phe 149 were observed between Tocotrienol and nsp16 (Figure 8D).Finally, Pereniporin B formed only one hydrophobic bond with Tyr 132 of nsp16 (Figure 8E).
These results indicate that the five phytomolecules selected in this study blocked the RNA binding site of nsp16 by binding with several amino acid residues of this site.However, only Capsicodendrin and Tocotrienol formed hydrogen bonds with Lys 46 and Lys 170 .Since these two residues form with Asp130 and Glu 203 the 4 residues of the 2'-O-MTase tetrad site, we conclude that these two phytomolecules are probably effective inhibitors of nsp16.

Discussion
Since the identification of COVID-19 in China in late December 2019, scientists have continuously searched for drugs and vaccines to eradicate this disease.Many drugs have been proposed and their efficacy has already been clinically evaluated.Among these, we can mention Remdesivir [22], Chloroquine and Hydroxychloroquine [23], Lopinavir and Ritonavir [24], Azythromycin [25] and many others [26].Several candidate vaccines have also been developed [27].Despite these efforts, variants of SARS-CoV-2 are still identified in various countries around the world [28].This confirms that COVID-19 will always remain a great problem for global health.
In Madagascar, the first case of COVID-19 was detected in March 2020 [29].Since then, many people tend to use medicinal plants and their by-products (like essential oils) for the treatment and/or prevention of this disease.
Examples are Artemisia annua, Eucalyptus globulus, Allium sativum, Zingiber officinalis and Cinnamosma fragrans.However, no conclusive research results have yet been able to prove, or even provide clear scientific explanations that these medicinal plants or their derived products contain any phytomolecules capable of treating COVID-19 or preventing SARS-CoV-2 infection.Therefore, the present study is conducted to identify phytomolecules with an inhibitory property against SARS-CoV-2 replication in some aromatics medicinal plants from Madagascar.Since in vitro and in vivo analysis processes are very expensive and time consuming, very costly and time consuming, we chose to use the molecular docking, one of bioinformatics or in silico method [30,31].Many researchers have also used this method in the search for drugs against SARS-CoV-2 [32][33][34][35].
First, we selected as ligands the seventy-six phytomolecules from sixteen aromatics medicinal plants from Madagascar (Supplementary Table 1).Most of them are monoterpenes and sesquiterpenes (Table 3).They are thus volatile compounds and major components of essential oils [36].In addition, they are well known for their antiplasmodial, antibacterial, antiviral, anti-inflammatory, and anticancer activity [37,38].Conversely, we chose as targets the five nsps including Mpro, PLpro, RdRp, Helicase and 2'-O-MTase of SARS-CoV-2 (Table 1).These nsps are very important in the replication of SARS-CoV-2 and are also highly conserved in these viruses [8,9,39,40].In addition, they are constantly targeted in the search for drugs against COVID-19 [41][42][43][44][45][46].Together, the selection of ligands and targets correspond greatly with the objective of this study, and also with the use of these plants in the COVID-19 pandemic.
Then, we predicted the active site residues of these five target nsps.In result, twenty-one amino acid residues are predicted in the active site of MPro (Figure 1A).This result is comparable to the results reported by other researchers [47,48].In contrast, eleven residues are predicted in the active site of PLpro (Figure 1B) and we did not predict the residues of the catalytic triad site (Cys 111 , His 272 and Asp 286 ) described by Osipiuk and colleagues [49].However, this triadic site is not considered a potential target in the search for PLpro inhibitors [50].Similarly, we did not predict the four key residues (D 618 , S 759 , D 760 and D 761 ) of the active site of RdRp [14].Nevertheless, we predicted five residues (Pro 809 , Glu 811 , Phe 812 , Cys 813 and Ser 814 ) that are very close to these key residues (Figure 2).Thus, the non-prediction of these keys residues has no effect on the docking results.In addition, we found sixteen residues, which are located in the ATP hydrolysis site and in the DNA binding site of the helicase (Figure 3A).These two sites are generally considered to be potential drug binding sites in helicase [15].Finally, we predicted eighteen residues that localize in the RNA binding site and SAM binding site of 2'-O-MTase (Figure 3B).Krafcikova and colleagues have previously reported that these two sites could be targeted in the search for inhibitors of this enzyme [16].
Finally, we performed molecular docking.We found that only five drimane sequiterpenes (Capsicodendrin, Ugandensolide, Cinnamolide, Tocotrienol, and Pereniporin B) interacted strongly with the five target nsps and were able to inhibit their functions (Table 5 and Figure 4, 5, 6, 7 and 8).Surprisingly, these are all secondary metabolites of Cinnamosma fragrans [51][52][53].This plant is one of the endemic medicinal plants of Madagascar and is well known by its name of "Mandravasarotra, Saro and Sakarivohazo" [53].Traditionally, it is used to treat respiratory problems [54].A decoction of its bark is also used to treat muscle pain and symptoms of malaria [52].In addition, its essential oil is well known for its antimicrobial properties [55] and for its use in the treatment of otorhinolaryngological diseases [54].
Recently, Pidoux and his colleagues have further indicated that the essential oils of this plant have an anti-inflammatory properties [56].These numerous pharmacological effects have inspired the Malagasy to give its name to "Mandravasarotra", which literally means "those who fight everything".These numerous properties have also motivated many Malagasy to use it in the treatment of various infectious diseases, including COVID-19.
In this in silico study, these five were found to be inhibitors of 5 nsps of SARS-CoV-2 (Table 4 and Figures 4, 5, 6, 7, and 8).Bearing in mind, previous studies have reported that Capsicodendrin, Ugandensolide, Cinnamolide, and Pereniporin B are α-glucosidase inhibiting agents [57].Tocotrienol is reported to be a rare form of vitamin E [58].But Williams and colleagues still indicated that α-glucosidase inhibitors have the potential to inhibit SARS-CoV-2 replication [59].For their part, Samad and colleagues also reported that vitamins A, D, E, and K may boost immune defenses and prevent complications of COVID-19, such as cytokine storm [60].Therefore, the five phytomolecules identified in this study may be both possible inhibitors of SARS-CoV-2 replication and may also have immunomodulatory effects.

Conclusion
In summary, this docking study revealed that Capsicodendrin, Ugandensolide, Cinnamolide, Tocotrienol and Pereniporin B from Cinnamosma fragrans or "Mandravasarotra, in Malagasy" can inhibit the five non-structural proteins of SARS-CoV-2.Thus, these phytomolecules may have the capacity to inhibit replication of these viruses.Given the previous knowledge of the various pharmacological properties of Cinnamosma fragrans, we can suggest that further analysis of these phytomolecules offers a new perspective in the research for antiviral drugs against COVID-19.Thus, further in vitro and in vivo studies are still needed to valorize these results.

Figure 1
Figure 1 Structures of the target proteins: (A) main protease or Mpro, (B) papain-like protease or PLpro.The subdomains that form Mpro and PLpro are shown by different colored ribbons.The active site residues predicted by COACH-D are shown as purple sticks

Figure 2
Figure 2 3D structures of the RdRp protein of SARS-CoV-2.The different subunits are shown in purple (nsp7), black (nsp8) and circled in blue (nsp12).The different sub-domains of nsp12 are also distinguised: β-hairpins (red), NIRAN (yellow), Interface (light green), Fingers (green), Palm (blue) and thumb (brown).The active site of the enzyme is surrounded by a red line and then expanded

Figure 4
Figure 4 Vizualisation of 3D and 2D interaction of 5 phytomolecules with Mpro.The subdomains of Mpro are presented in hydrophobicity while the 5 phytomolecules are presented as sticks: (A) Capsicodendrin, (B) Ugandensolide, (C) Cinnamolide, (D) Tocotrienol and (E) Pereniporin B. The different interactions modes of these phytomolecules with the residues of the active site of MPro are also represented: hydrogen bonds, hydrophobic bonds and pi-cation bond are colored in green, purple and beige respectively.Non-favorable interactions are shown as red lines.

Figure 5
Figure 5 Vizualisation of 3D and 2D interaction of 5 phytomolecules with PLpro.The subdomains of PLpro are shown in hydrophobicity, while the 5 phytomolecules are shown as sticks: (A) Capsicodendrin, (B) Ugandensolide, (C) Cinnamolide, (D) Tocotrienol and (E) Pereniporin B. The different interactions modes of these phytomolecules with the residues of the active site of the enzyme are also represented: hydrogen bonds, hydrophobic bonds and pi-cation bond are colored in green, purple and beige respectively.Non-favorable interactions are shown as red lines

Figure 6
Figure 6 Vizualisation of 3D and 2D interaction of 5 phytomolecules with RdRp.The subdomains of RdRp are presented in hydrophobicity while the 5 phytomolecules are presented as sticks of different colors: (A) Capsicodendrin, (B) Ugandensolide, (C) Cinnamolide, (D) Tocotrienol and (E) Pereniporin B. The different modes of interaction of these phytomolecules with the residues of the active site of the enzyme are also represented: the hydrogen bonds, the hydrophobic bonds and the pi-cation bond are colored in green, purple and beige respectively Helicase

Figure 7
Figure 7 Visualization 3D and 2D of interaction 5 phytomolecules with helicase: The subdomains of the helicase are presented in hydrophobicity while the 5 phytomolecules are presented as sticks of different colors: (A) Capsicodendrin, (B) Ugandensolide, (C) Cinnamolide, (D) Tocotrienol and (E) Pereniporin B. The different modes of interactions of these phytomolecules with the residues of the active site of the enzyme are also represented: hydrogen bonds, hydrophobic bonds and pi-cation bond are colored in green, purple and beige respectively.Non-favorable interactions are shown as red lines 2'-O-MTase

Figure 8
Figure 8 Visualization 3D and 2D of interaction 5 phytomolecules with 2'-O-MTase.The 5 phytomolecules are presented as different colored sticks: (A) Capsicodendrin, (B) Ugandensolide, (C) Cinnamolide, (D) Tocotrienol and (E) Pereniporin B. The different modes of interactions of these phytomolecules with the residues of the active site of the enzyme are also represented: hydrogen bonds, hydrophobic bonds and pi-cation bond are colored in green, purple and beige respectively.Non-favorable interactions are shown as red lines

Table 2
X, Y, Z coordinates of the grid box

Table 3
Classification and 2D structures of the 76 phytomolecules used in this study

Table 4
Molecular docking data represented the 5 phytomolecules with best affinity with 5 SARS-CoV-2 targets