The outbreak of novel coronavirus in Wuhan region of China has become pandemic. The origin of the virus is currently unknown, but few researchers claim that it is a type of coronavirus from bat origin, some claims that it came from fishes to humans [3,40,41,42]. There were also controversial statements that it was made in a laboratory or otherwise engineered and after research the statement got contradicted by the Scripps Research Institute and stated that the virus has natural origin [43]. The literatures have very few information about the mechanism of action and even the detailed information about the genetic material and proteins of SARS-CoV-2 is in scarce. The situation is becoming worse day by day as the therapeutics for the COVID-19 is not available yet. The drug repurposing strategy is being used to somehow cure of the patients. Recently few drugs have been sent for clinical trials and few of them have even passed second stage. The drug and vaccine discovery process is still on and no lead has come in market as an armamentarium against the disease [16,44] till date. Therefore, there is a need of therapeutics still persist. The compounds derived from plants have gain much more acknowledgement in recent time and hence can be used as possible solution against the disease. Molecular docking is the finest way to predict the binding affinities of compounds and hence, plays a pivotal role in discovery and development of drugs [45].
The novel corona virus has viral genome which encodes for the 20 proteins, which includes two protease PLpro and 3CLpro/Mpro) that plays a crucial role in viral replication and gained tremendous attention as a drug target. In the current study, these two proteases have been taken as a potential target [46]. Eighteen phytocompounds from the three medicinal plants viz. E. harmandiana, S. flavescens and A. paniculate were considered for the molecular docking analysis (Table 1). Chloroquine, Oseltamivir, Remdesivir and Ribavirin has been used as a control. These drugs have been recently used in the treatment of the COVID-19 patients and are in clinical trial. There is no potential drug molecule approved by the FDA and this is the only reason that these repurposed drugs have been taken as a control in the current study. Chloroquine is an antimalarial drug is being used in combination with Azithromycin for the treatment of COVID patients [47]. Oseltamivir in combination with hydroxychloroquine was also found to inhibit the coronavirus to some extent [48,49]. Remdesivir and ribavirin are the FDA-approved anti-RdRp drugs that was found to treat patients and reduce the danger of the mysterious new viral infection COVID-19 [50]. Binding energies of various natural occurring phytochemicals were obtained through AutoDock Vina. The interaction of inhibitor and protein receptor were predicted in 2D and 3D, with the help of BIOVIA Discovery study visualizer. The docked poses clearly show that drug molecules and phytocompounds bind the active sites of SARS-COV-2 macromolecule structures.
Interaction with PLpro
Panicoline binds firmly with the residue GLY160 through conventional hydrogen bond, GLN269 GLY160 through carbon-hydrogen and Van der Waals with the surrounding residues of the PLpro protein of SARS-COV-2 (Figure 1a). 14-Deoxy-11,12-didehydroandrographolide stabilizes the active site through conventional hydrogen bond (GLN269), carbon hydrogen bond (GLY160) and Van der Waals interaction with rest residues (Figure 1b). Canthin-6-One 9-O-Beta-Glucopyranoside append within the active site of SARS-COV-2 through Pi-anion interaction with residues GLU161, conventional hydrogen bond with residue LEU162, GLY160, ASN109, Pi donor hydrogen bond with LEU162 and Van der Waals interaction with the rest (Figure 1c). Andrographine secured the active sites with amide-pi stacked interaction with residues GLY161, conventional hydrogen bond with ASN109, carbon hydrogen bond with ASP108, pi-alky, alkyl interaction with the residues LEU162, HIS89, VAL159 and Van der Waals interaction with the surrounding residues (Figure 1d). Andrographolide adhere within the active sites through conventional hydrogen bond (VAL159 and GLN269) and with the Van der Walls interaction with the rest residues as shown in Figure 1(e). 5-Hydroxy-7,8,2',3'-Tetramethoxyflavone firmly stabilizes the active sites through amide pi-stacked interaction with residues GLY160, conventional hydrogen bond with ASN109, carbon hydrogen bond with ASP108, GLN269, further it undergoes alkyl, pi-alkyl interaction with residues LEU162, VAL159, HIS89 and through Van der Waals interaction with the rest (Figure 1f). Neoandrographolide binds with the active sites through conventional hydrogen bond (ASN109, GLN269, VAL159) and through carbon hydrogen bond (GLY160, THR158) (Figure 1g). Paniculide-A stabilizes the active site of the PL pro through alkyl interaction with residues VAL159 and conventional hydrogen bond with residues ASN109 (Figure 1h). The 5-Hydroxy-7,2',3'-Trimethoxyflavone cohere with the active sites with residues LEU162, VAL159, HIS89 through alkyl, pi-alkyl interaction, pi-anion interaction with residue GLY160, conventional hydrogen bond with residues THR158, ASN109 and carbon hydrogen bond with residues ASN109 and with rest through Van der Walls interaction as shown in Figure 1(i). 5,7,2′,3′-tetramethoxyflavanone forms several noncovalent interaction at the active site, it forms conventional hydrogen bond with THR158, ASN109, carbon hydrogen bond with residue GLN269, alkyl and pi-alkyl bond with LEU162, HIS89, VAL159 and pi-anion interaction with residue GLU161 (Figure 1j). Deoxyandrographolide stabilizes the active site only through single conventional hydrogen bond (GLN269) and surrounding residues with Van der Waals interaction (Figure 1k). Kushenol W form pi-sigma interactions with GLU161, pi alkyl bond with LEU162, conventional hydrogen bond with GLY160 carbon hydrogen bond with residues ASP108 and GLY160 (Figure 1l). The Kushenol K forms conventional hydrogen bonds with LEU162, ASN109, carbon-hydrogen bond with VAL159 and Van der Waals interaction with the surrounding residues (Figure 1m). 5-Hydroxy-7,8,2'-trimethoxyflavone 5-glucoside secure the active site through amide pi stacked interactions with residues GLY160, pi-anion interaction with GLU161 and conventional hydrogen bond with GLN269, ASN109 (Figure 1n).
Deoxyandrographolide19β-D-glucoside cohere active sites through conventional hydrogen bond with residue THR158, carbon hydrogen bond with residues GLY160, ASP108 and alkyl bond with residue LEU162 and it is depicted in form of 2D representation in Figure 1(o). Paniculide-B forms alkyl bond with VAL159, conventional hydrogen bond with ASN109, GLY160, GLN269, and carbon hydrogen bond with GLN269 and where Paniculide-C secure the active sites with alkyl (LEU162), conventional hydrogen bond (ASN109) (Figure 1p and 1q). The interaction analysis of 14-Deoxy-11-oxoandrographolide depicts that it cohere the active sites through conventional bond with residues LEU162, ASN109 and GLN269 (Figure 1r).
Van der Wall interactions and hydrogen bonding play a major role in the binding process. Van der Wall interaction is a weakest intermolecular attraction between two molecules. Though it is the weakest bond between two objects, but a lot of Van der Wall forces can make the interaction very strong [51]. In the protein ligand interactions, the hydrogen bond helps the ligand to stabilize but there are also other interactions such as hydrophobic or Van der Wall interactions that helps in stabilization of the nonpolar ligands too. An analysis of the structure of ligands and docked poses usually helps in understanding the interactions and the binding energy establishes which of the compound is important. Based on these basics the molecular docking program is most widely used tool in the drug discovery process as the result suggests the potential drug compound based on least binding energy [52]. The comparison of the estimated free energy of binding (∆G) or binding affinity inferred that the Canthin-6-One 9-O-Beta-Glucopyranoside (-9.4 kcal/mol) have the least binding energy among the studied plant natural components and can be a potential drug against the PLpro of SARS COV-2. The order of binding energy of other studied plant natural components is as follows: 5-Hydroxy-7,8,2'-trimethoxyflavone 5-glucoside (-8.8 kcal/mol) > 14-Deoxy-11-oxoandrographolide (-8.7 kcal/mol) > Kushenol K and Neoandrographolide (-8.6 kcal/mol) > Kushenol W (-8.4 kcal/mol) > 14-Deoxy-11,12-didehydroandrographolide (-8.2 kcal/mol) > Deoxyandrographolide (-8.1 kcal/mol) > Paniculine (-8.0 kcal/mol) > Andrographolide and Deoxyandrographolide19β-D-glucoside (-7.9 kcal/mol) > 5-Hydroxy-7,8,2',3'-Tetramethoxyflavone and Andrographine (-7.6 kcal/mol) > 5,7,2′,3′-tetramethoxyflavanone and 5-Hydroxy-7,2',3'-Trimethoxyflavone (-7.5 kcal/mol) > Paniculide-B (-7.2 kcal/mol) > Paniculide-A (-7.1 kcal/mol) > Paniculide-C (-6.7 kcal/mol). The analysis of binding energies suggests that all the binding energy falls between -6.7 to 9.4 kcal/mol and 2D interaction in Figure 1(a-r) depicts that the studied phytocompounds have a lot of hydrogen bond and Van der Walls interaction that suggests that the ligands are stabilized within the complex.
Interaction with Mpro/3CLpro
The Panicoline secures active sites of the main protease (Mpro or 3CLpro) through conventional hydrogen bond and carbon hydrogen bond with residues ASN151, THR111, GLN110, SER158 and ILE152 respectively (Figure 2a). 14-Deoxy-11,12-didehydroandrographolide forms conventional hydrogen bond with residues THR111 and pi-alkyl interaction with ILE249 and van der Waals interaction with the surrounding residues (Figure 2b). Canthin-6-One 9-O-Beta-Glucopyranoside binds firmly with the active sites through conventional hydrogen bond with residues THR111, ASP295, THR292 and pi-alkyl bond with VAL202 (Figure 2c). Andrographine adhere within the active sites through conventional hydrogen bond with the residue THR292, pi-pi stacked interaction with the residue PHE294 and pi-alkyl bond with PRO293, ILE294 (Figure 2d). Andrographolide forms conventional hydrogen bond with residue ASN151, pi-sigma bond with residue PHE294 and van der Waals interaction with the surrounding residues (Figure 2e). Neoandrographolide forms conventional hydrogen bond with the residues ASP295, THR111 and pi alkyl interaction with residues VAL202, PRO293 and ILE249 (Figure 2f). Paniculide-A cohere the active sites of the main protease (MPRO or 3CLPRO) with conventional hydrogen bond and alkyl,pi-alkyl interaction with the residues GLN110, THR111, THR292 and ILE249, PHE294, PHE8 respectively (Figure 2g). 5-Hydroxy-7,8,2',3'-Tetramethoxyflavone adhere with the active sites through conventional hydrogen bond (ASN151 and THR111), pi donor hydrogen bond (THR292), pi-pi-stacked (PHE294), pi- alkyl interaction with residues PRO293, ILE294, PHE294 and are depicted in Figure 2(h). 5,7,2′,3′-tetramethoxyflavanone forms Pi alkyl interaction, conventional hydrogen bond pi-pi stacked interaction with residues ILE249, THR111 and PHE294 respectively (Figure 2i). 5-Hydroxy-7,2',3'-Trimethoxyflavone stabilizes the active sites through conventional hydrogen bond (ASN151 and THE111), pi donor hydrogen bond (THR292), pi-pi stacked interaction (PHE294), alkyl, pi-alkyl interaction (PHE294, ILE249, HIS246 and PRO293) and Van der Waals interaction with the surrounding residues and the interactions can be seen in Figure 2(j). With a good efficiency of binding Deoxyandrographolide forms conventional hydrogen bond with ASN151 and pi-alkyl with PHE249 (Figure 2k). Kushenol W cohere with active sites residues THR111 through conventional hydrogen bond, pi-pi stacked interaction (PHE294) and pi alkyl interactions (ILE249 and PRO293) (Figure 2l). 5-Hydroxy-7,8,2'-trimethoxyflavone 5-glucoside forms conventional hydrogen bond with residue GLN110, Pi-sigma interaction (PHE294), pi-pi interaction with PHE294, alkyl, pi-alkyl interaction with VAL297, PRO293, ILE249 and carbon hydrogen bond with ILE249 (Figure 2m). Kushenol K stabilizes the active site with residues PHE294 through pi-pi stacked interaction, pi-pi sigma interaction (ILE249) and pi-alkyl interacions (PRO293 and PHE294) (Figure 2n). The Deoxyandrographolide19β-d-glucoside forms conventional hydrogen bond with residue THR21, THR26, GLN69, ILE249 and carbon hydrogen bond with ASP245 (Figure 2o). Paniculide-B cohere with the active sites through conventional hydrogen bond (THR292, THR111 and GLN110) and alkyl interaction (PHE8 and PHE294) whereas Paniculide-C forms conventional hydrogen bond with THR111 and GLN110; alkyl and pi alkyl interaction with PRO293, HIS246, ILE249, VAL202 and the interactions are depicted in Figure 2(p and q). In the case of 14-Deoxy-11-oxoandrographolide, it stabilizes the active sites with residue GLN269, ASN109 and LEU162 through conventional hydrogen bond, alkyl bond with ILE249 and through Van der Waals interaction with the rest residues (Figure 2r).
The least binding energy of Canthin-6-One 9-O-Beta-Glucopyranoside (-8.5 kcal/mol) obtained from molecular docking study suggests that the molecule have good binding affinity against the Mpro or 3CLpro. The order of other molecules as per free energy binding (∆G) is as follows: Neoandrographolide (-8.4 kcal/mol) > Kushenol W (-7.3 kcal/mol) > 14-Deoxy-11,12-didehydroandrographolide and 14-Deoxy-11-oxoandrographolide (-7.1 kcal/mol) > 5-Hydroxy-7,8,2'-trimethoxyflavone 5-glucoside & Andrographolide (-6.9 kcal/mol) > 5-Hydroxy-7,2',3'-Trimethoxyflavone (-6.8 kcal/mol)> 5,7,2′,3′-tetramethoxyflavanone, 5-Hydroxy-7,8,2',3'-Tetramethoxyflavone, Andrographine and Paniculine (-6.5 kcal/mol) > Kushenol K (-6.4 kcal/mol) > deoxyandrographolide19β-d-glucoside or diterpene glucoside (-6.2 kcal/mol) > Paniculide-A (-6.1 kcal/mol) > Paniculide-C (-6.0 kcal/mol) Paniculide-B (-5.9 kcal/mol). The 2D and 3D interaction is depicted in the Figure 2 (a-r).
Interaction with control drugs
The docked pose of minimum energies conformers of four control drugs Chloroquine, Oseltamivir, Remdesivir and Ribavirin. Figure 3 (a-d) shows chloroquine binds firmly with PLPRO active site and form conventional hydrogen bond with THR158 residue and carbon hydrogen bond with residue GLU161 and VAL159. Oseltamivir stabilizes within active site through conventional bond with residue ASN109, carbon hydrogen bond with residue GLY160 and alkyl interaction with residue LEU162. Remdesivir binds to the active site through pi-anion (GLU161), amide-pi stacked interaction (VAL159 and GLY160), conventional hydrogen bond (ASN109) and pi-alkyl interaction (LEU162). Ribavirin forms conventional hydrogen bond with residue GLY160, GLN269, LEU162, ASN109, carbon hydrogen bond with residue GLN269, ASN109 and among all the interactions Van der Walls interaction plays a major role. The comparison of binding affinity or estimated free energy (∆G value) of binding shows that the Remedisivir (-8.4 kcal/mol) have least binding energy with active sites of the PLpro. The order of binding energy of other drugs with PLpro is as follows: Ribavirin (-6.8 kcal/mol) > Oseltamivir (-6.4 kcal/mol) > Chloroquine (-6.3 kcal/mol).
Interactions of the drugs with the Mpro/3CLpro shows that chloroquine firmly binds within the active sites through pi-anion interaction with the residues ASP295, pi-pi stacked interaction with residues PHE294 and pi-alkyl interaction with residue PHE294 and carbon hydrogen bond with residue THR111. It doesn’t form any hydrogen bonds within the active site. Ribavirin forms conventional hydrogen bond with residues GLN110, PHE294, THR111, THR292. Oseltamivir stabilises the pi- alkyl interaction with PHE294 and conventional hydrogen bond with residues GLN110, THR111 and ASN151. Remdesivir cohere the active site through conventional hydrogen bond (GLN110, ASN151 and PHE294) and pi-alkyl interaction (ILE249, PRO252, VAL297 and PRO293) with the active sites of Mpro/3CLpro. Pi – interaction plays a major role in stability of a particular drug within the active site [68]. The binding affinity of the drugs with Mpro/3CLpro suggests that the Remdesivir have high affinity to inhibit the protein with most negative ∆G value i.e. - 8.3 kcal/mol and all the other studied drugs showed similar ∆G value i.e. -5.8 kcal/mol, the 3D and 2D interactions of drugs with the active sites of Mpro/3CLpro are depicted in Figure 4 (a-d).
Pharmacokinetics
ADMET stands for Absorption, Distribution, Metabolism, Excretion and Toxicity. The prediction of the ADMET properties plays an important role in the drug discovery and development. The absorption of drugs depends on membrane permeability, intestinal absorption, skin permeability levels, P-glycoprotein substrate or inhibitor. The distribution of drugs depends on factors that include the blood–brain barrier (logBB), CNS permeability, and the volume of distribution (VDss). Metabolism is predicted based on the CYP models for substrate or inhibition (CYP2D6, CYP3A4, CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4). Excretion is predicted which is based on the total clearance model and renal OCT2 substrate. The toxicity of drugs is predicted based which is on AMES toxicity, hERG inhibition, hepatotoxicity, and skin sensitization. These parameters were calculated and checked for compliance with their standard ranges [54]. Properties such as ADMET profiling of compounds were determined using SWISS ADME [http://www.swissadme.ch/, 53]. Intestinal epithelium barrier/gut–blood barrier is a barrier that is crucial barrier for all the compounds to overcome. Intestinal epithelium barrier regulates nutrients absorption, water and ion fluxes, and denotes the first defensive barrier against toxins and enteric pathogens and the gut-blood barrier (GBB) controls the passage of drugs from intestinal lumen to the bloodstream. Except Kushenol K, GI absorption of all the phytochemicals were high which means that it was predicted to be absorbed easily in gut and intestine epithelium. Distribution of compounds through various compartments of the body was accessed using its Blood-brain barrier (BBB) penetration [55]. Among all the phytocompounds only Panculide-A, Andrographine, Deoxyandrographolide, 5,7,2′,3′-tetramethoxyflavanone, 5-Hydroxy-7,2',3'-Trimethoxyflavone are predicted to have blood brain barriers penetration. P glycoprotein is a drug transporter having broad substrate specificity, Drugs that are substrates of P-gp are subject to low intestinal absorption, low blood-brain barrier permeability, and face the risk of increased metabolism in intestinal cells. 14-Deoxy-11,12-didehydroandrographolide, 5-Hydroxy-7,8,2'-trimethoxyflavone 5-glucoside, Andrographolide, Paniculine A, Neoandrographolide, Kushenol K, 14-Deoxy-11-oxoandrographolide, Deoxyandrographolide are predicted to have affinity for p-glycoprotein. The result shows that except these phytochemicals rest phytochemicals may act as a non-substrate of p-glycoprotein [56]. Metabolism mainly depends on the CYP450 enzyme and its iso forms which are CYP 3A4, 2D6, 1A2, 2C9 and 2C19. These enzymes are responsible for the detoxification of drugs passing the liver. Therefore, any compound blocking P450 can cause toxicity. Out of all the 18 compounds 5-Hydroxy-7,8,2'-trimethoxyflavone 5-glucoside, Neoandrographolide, Kushenol W, Kushenol K, Andrographine, 5-Hydroxy-7,8,2',3'-Tetramethoxyflavone, 14-Deoxy-11,12-didehydroandrographolide, 5,7,2′,3′-tetramethoxyflavanone, 5-Hydroxy-7,2',3'-Trimethoxyflavone compounds block the enzyme responsible for detoxification and hence, can be responsible for toxicity. Skin permeation coefficient (log Kp) is the measure of skin to absorb a certain drug or chemical. In the given table 2, log kp of skin permeation of all the compounds lies between the standard value of log Kp -8.0 to -1.0 cm/s except 5-Hydroxy-7,8,2'-trimethoxyflavone 5-glucoside, Deoxyandrographolide19β-D-glucoside, Paniculine, which shows that these possess an ability to absorb less in the membrane [57].
ADMET study of all these molecules suggested that the molecules Canthin-6-One 9-O-Beta-Glucopyranoside, deoxyandrographolide 19β-d-glucoside or diterpene glucoside, Paniculide-B, Paniculide-C have passed all the barriers of ADMET and indicated that these molecule can be a successful drug molecule. All these compounds have high gastrointestinal absorption which is an important and decision making standard of oral dosing, this implies that the phytocompounds can be used as an oral drug. These drugs also passed the blood brain barrier (BBB) permeability test, therefore, these compounds qualifies a fundamental index of drug distribution. High negative value of log Kp suggests that the phytocompounds have less skin permeation. Binding of CYP450 enzyme may cause degradation of phytocompounds inside the body and can lead to toxicity. Bioavailability of these compounds are high and it indicates high potential as drug molecule. The above mentioned parameters for all these molecules are in the range found for successful drug molecule (Table 2).
Potential drug against COVID 19
The molecular docking studies have been carried out using 19 phytocompounds that might act as potential drug against SARS-CoV-2 Mpro/3CLpro and PLpro. The analysis of molecular interaction between the active sites of the studied protein and the phytocompounds suggested that these compounds can inhibit the protein and will block the viral replication. The active site of Mpro/3CLpro consists of residues THR21, THR26, GLN69, GLN110, THR111, ASN151, HIS246, ILE249, THR292 and ASP295 whereas the active site residues for PLpro are ASN109, THR158, VAL159, GLY160, LEU162 and GLN269 (Table 3). The Canthin-6-One 9-O-Beta-Glucopyranoside in comparison with the control drugs, was found showing least binding energy with active sites of both the target proteins i.e. Mpro/3CLpro and PLpro. The distance between the ligand and catalytic residues of the protein shows that the Canthin-6-One 9-O-Beta-Glucopyranoside interact within the active site of the protease proteins and have high affinity of binding. The ADMET study also suggest that the Canthin-6-One 9-O-Beta-Glucopyranoside have all the drug like properties and can be considered as a potential drug against the infection caused by human SARS coronavirus-2.
Table 3. Tabular representation of conventional hydrogen bonding and its length in protein ligand interactions
|
Name
|
SARS COV Protein 1(3CLpro)
|
SARS COV Protein 2 (PLpro)
|
|
Vital residues for H-bond formation
|
Length
(in Å)
|
Vital residues for H-bond formation
|
Length
(in Å)
|
|
Panicoline
|
ASN151
THR111
GLN110
|
1.99
3.00
3.12
|
GLY160
|
1.87
|
|
14-Deoxy-11,12-didehydroandrographolide
|
THR111
|
3.08, 2.94
|
GLN269
|
2.72
|
|
Canthin-6-One 9-O-Beta-Glucopyranoside
|
THR111
THR292
ASP295
|
2.00, 2.67
2.77
2.23
|
LEU162
GLY160
ASN109
|
3.05
2.16
2.99
|
|
Andrographine
|
THR111
ASN151
|
3.20, 2.97
2.14
|
ASN109
|
3.02
|
|
Andrographolide
|
ASN151
|
2.46
|
VAL159
GLN269
|
2.63
1.99, 2.51
|
|
Neoandrographolide
|
THR111
ASP295
|
3.13, 2.71, 2.31
2.46
|
GLN269
ASN109
VAL159
|
2.84, 2.08
2.68, 2.88, 3.08
3.17
|
|
Paniculide-A
|
GLN110
THR111
THR292
|
3.28
2.89, 3.27
2.94
|
ASN109
|
3.00, 3.06
|
|
5-Hydroxy-7,8,2',3’-
Tetramethoxyflavone
|
THR111
ASN151
|
2.99, 3.14
2.11
|
ASN109
|
3.31
|
|
5,7,2′,3′-tetramethoxyflavanone
|
THR111
|
3.29, 3.12
|
THR158
ASN109
|
3.13
3.13
|
|
5-Hydroxy-7,2',3'-Trimethoxyflavone
|
ASN111
ASN151
|
3.07, 3.17
2.60
|
THR158
ASN109
|
3.02
3.11
|
|
Deoxyandrographolide
|
ASN151
|
3.02
|
GLN269
|
3.12
|
|
Kushenol W
|
THR111
|
3.08
|
GLY160
|
1.79
|
|
5-Hydroxy-7,8,2'-trimethoxyflavone
5-glucoside
|
GLN110
|
3.27
|
ASN109
|
3.31
|
|
Kushenol K
|
NO INTERACTION
|
LEU162
ASN109
|
3.14, 3.23
2.58
|
|
Deoxyandrographolide19β-
d-glucoside
|
THR21
GLN69
THR26
ILE249
|
2.74
3.08, 3.00
2.59, 2.49
2.70
|
THR158
|
2.99
|
|
Paniculide-B
|
GLN110
THR292
THR111
|
3.29
2.94
2.89, 3.33
|
ASN109
GLY160
GLN269
|
3.20, 3.11, 2.80
2.73
3.37
|
|
Paniculide-C
|
THR111
GLN110
|
3.33, 3.19
2.81
|
ASN109
|
3.05, 3.25
|
|
14-Deoxy-11-oxoandrographolide
|
GLN110
HIS246
THR111
|
3.10
2.82
2.76
|
LEU162
GLN269
ASN109
|
2.89
1.98
3.05
|
Das [58] studied 33 molecules through the help of docking approach, and find out that these molecules could bind near the Cys145 and His41 (catalytic residue) of the main protease. Salim [59] reported that α- hederin and Nigellidine are the major phytochemical obtained from Nigella sativa which are capable in restricting SARS-CoV-2 with great energy score as compared to clinical drugs on the basis of molecular docking. Muralidharan [11] performed molecular dynamics (MD) simulations in order to evaluate the interconnection among the protein and three drugs. The RMSD (root-mean-square-deviation) of interconnection is found to be 3Å and remain firm while the simulations. Therefore, the amalgam of ritonavir, lopinavir, and oseltamivir are greatly efficacious against the protease of SARS-CoV-2, and these agents can be surveyed further for drug reusing purpose for the victorious restriction of SARS-CoV-2. Joshi [9] identified some natural compounds such as phyllaemblicin B, hesperidin, biorobin, afzelin, nympholide A, lacticopicrin 15-oxalate, myricitrin, nympholide A, and d-viniferin from the screening of ~7100 molecules which proved as a strong binders not only for proteases but also for other targets (RNA dependent RNA polymerase, and human angiotensin-converting enzyme of SARS-CoV-2. Adeoye [6] determined the inhibitory potentiality of chloroquine, lopinavir, remdesivir, ribavirin, azithromycin, and oseltamir towards viral proteases, V-ATPase, SARS-CoV spike glycoprotein/ACE-2 complex, and protein kinase A. It was evaluated that, lopinavir has the greatest affinities for the 3-chymotrypsin like protease, cyclic AMP-dependent protein kinase A, and SARS-CoV spike glycoprotein/ACE-2 complex whereas remdesivir has shown affinities for papain-like proteins, and vacuolar proton-translocating (V-ATPase), and chloroquine has affinities for cyclic AMP-dependent protein kinase A, and 3-chymotrypsin-like protease in comparison to ribavirin and oseltamivir [60]. Aanouz [61] used the docking process for examining the interaction type and affinity at the binding site among the 67 compounds and the SARS-CoV-2 proteases. The results showed that, only three molecules (b-Eudesmol, Crocin, and Digitoxigenin) are found as inhibitors in the control of SARS-CoV-2). Enmozhi [69] evaluated out andrographolide from A. paniculata as a main protease inhibitor in case of SARS-CoV-2 through in silico studies. Kumar [62,63] carried out molecular docking study of FDA approved drugs that are used in the cure of different viral ailments in order to investigate their binding affinity for the active site of Mpro [64]. Docking studies determined that drugs raltegravir, tipranavir, and lopinavir-ritonavir among others particularly binds to the protease with similar affinity as of the α-ketoamide inhibitors [11]. From the earlier time, herbal plants products are successfully employed for the cure of several viral disorders. Many of the promising lead natural compounds of our investigation are anti-virals, therefore, there is a big probability that these bioactive constituents would be appropriate in the control of SARS-CoV-2 and could be helpful for the discovery of multi-targeted agent against the SARS-CoV-2 COVID19 infection [65].
The hunt for plant-derived antiviral for the control of SARS-CoV-2 is hopeful, as many plants have been reported to be effective against Beta coronaviruses [66,67]. Many reports to recognize the promising inhibitors of SARS-CoV-2 from plants have been published by using a computational approach (Das, 2020). In the present study, after evaluating the multiple medicinal properties of the natural products, a total 18 compounds (Canthin-6-one 9-O-beta-glucopyranoside from E. harmandian; Kushenol W, and Kushenol K from S. flavescens; and 3α, 14, 15, 18-tetrahydroxy-5β, 9βH, 10α-labda-8, 12-dien-16-oic acid γ-lactone, deoxyandrographolide, neoandrographolide, 14-deoxy-11, 12-didehydroandrographolide, deoxyandrographolide19β-d-glucoside, 5,7,2′,3′-tetramethoxyflavanone, 5-hydroxy-7,2′,3′-trimethoxyflavone, 14-Deoxy-11-oxoandrographolide, 5-Hydroxy-7,8,2',3'-Tetramethoxyflavone, 5-Hydroxy-7,8,2', Trimethoxyflavone, Andrographine, Panicoline, Paniculide-A, Paniculide-B, Paniculide-C from A. paniculate) were screened out for determining their inhibitory potentiality against Mpro and PLpro by molecular docking analysis.