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\begin{document}

\title{Identification of Promising SARS-CoV-2 Main Protease (Mpro) and Spike
Protein Inhibitors From Edible Mushroom: A Computational Approach}



\author[1]{Sukanth Kumar Enmozhi}%
\author[1]{Kavitha Raja}%
\author[1]{Kaleeswaran M}%
\author[2]{Rahul Vivek}%
\author[3]{Rachel Stepheena Samuel}%
\author[4]{Irudhayasamy Sebastine}%
\author[1]{Ramdurai Murugan}%
\author[5]{Jerrine Joseph}%
\author[1]{Arulvasu Chinnasamy}%
\affil[1]{University of Madras - Guindy Campus}%
\affil[2]{Government of Maharashtra Food and Drug Administration}%
\affil[3]{Bharathidasan University}%
\affil[4]{Madurai Medical College College of Pharmacy}%
\affil[5]{Sathyabama Institute of Science and Technology}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Coronaviruses infect lungs leading to death due to asphyxiation.
SARS-CoV-2 is treated by targeting symptoms, repurposing drugs and
plasma therapy. Several synthetic drugs are being prescribed that cause
major side effects in liver, kidney and heart. Therefore new compounds
with low toxicity must be investigated. We have identified antiviral
compounds like Eritadenine, Gallic Acid, Ergosterol Peroxide and Pleuran
from various edible mushrooms such as \emph{Lentinula edodes},
\emph{Agaricus bisporus}, \emph{Pleutorus ostreatus} and \emph{Hericium
erinaceus} with evidence of literature review. The docking and
simulation studies with the targets of SARS-CoV-2 such as Main Protease
(M Pro) and Spike Protein were highly successful. \emph{In silico} ADMET
studies further proved that these compounds are druggable with low
toxicity. These compounds have potential to prevent the cellular entry
to prohibit assembly of new viruses inside the cell. But further studies
are required to substantiate their bioactivity claim by \emph{in vitro}
and \emph{in vivo} assay methods.%
\end{abstract}%



\sloppy


\textbf{1. INTRODUCTION:}

Nidovirales is the order from which the family of coronaviridae are
classified they are further subdivided into four genera namely, \selectlanguage{greek}α, β, γ
\selectlanguage{english}and \selectlanguage{greek}δ. \selectlanguage{english}The virus SARS-CoV-2 which has caused global pandemic and havoc
is of the \selectlanguage{greek}β \selectlanguage{english}genera of the coronaviridae family, which has four protein
constructs where its frame is made of Nucleocapsid protein (N) which
encompasses the single stranded viral RNA (ssRNA), Membrane protein (M),
Envelope protein (E) and spike protein (S) \textsuperscript{1}. These
proteins are replicated and multiple copies of the virus are produced
within the human cell as per the well-known mechanism as described: The
spike protein of the SARS-CoV-2 virus attaches to the Angiotensin
Converting Enzyme-2 (ACE-2) and with host factors as Cell Surface Serine
Protease (TMPRSS-2) and enters the cell resulting in the release of the
viral contents to the cell cytoplasm in which the viral ssRNA is
spontaneously translated as individual non- structural proteins which
act as regulatory proteins along with protective vesicles which contain
genomic RNA and subgenomic mRNA for viral replication and transcription.
And the resultant structural proteins move towards the endoplasmic
reticulum which in-turn produces newly replicated viral genomic RNA and
the viral structural construct when transporting through the Endoplasmic
Reticulum to Golgi Intermediate Compartment (ERGIC) and the newly made
viral constructs are released out of the cell via
exocytosis\textsuperscript{2}. SARS-CoV-2 infection causes COVID-19
which is an upper respiratory infection emerged from Wuhan, China also
it spread as a pandemic leading to more than 208 million cases, 4.3
million deaths and 186 million recoveries worldwide \textsuperscript{3}.

The production of more number of viral particles then results in the
increased infection and lysis of the alveolar epithelial cells, Type I
and II pneumocytes following cytokine storm and inflammatory reaction in
the lungs thereby leading to Acute Respiratory Distress Syndrome (ARDS).
The recoveries from COVID- 19 were made possible through treatment of
symptoms, repurposing drugs, convalescent plasma therapy, and artificial
oxygen supply to the patients. SARS-CoV-2 mainly causes damage in the
lungs due to high concentration of ACE-2 receptors and presents drastic
effects in the advanced stages of the disease progression as shock,
ARDS, hypoxemia, coagulation defects, encephalopathy, acute kidney
injury and heart failure resulting to the death of the affected person.
The patients with symptoms are diagnosed with Reverse Transcriptase
Polymerase Chain Reaction (RT-PCR), Basic blood work, Chest X ray, High
Resolution Computer Tomography Chest, Serology and classified into five
groups based on their severity of infection which are: Asymptomatic or
Pre-symptomatic infection, Mild infection, Moderate infection, severe
infection and Critical infection \textsuperscript{4}.

Treatments proposed according to the infection rate are: Mild infection
the treatment for the symptoms is given and for Moderate infection
treatment of symptoms is given individually or along with antibacterial
medication only if a bacterial infection can be seen. For treatment with
severe infection and critical infection the supplemental oxygen or
non-invasive ventilation along with treatment of symptoms and
interleukin 6 blockers (IL-6 Blockers), Ivermetcin, Hydroxychloroquine,
Lopinavir or Ritonavir, Remdesivir and systemic corticosteroids are
given according to the systemic evaluation or national health
guidelines. However, these drugs are advised to be used with extreme
caution as it may cause severe side effects and permanent damage the
major organs such as kidney, liver and heart \textsuperscript{5}.

Due to these reasons natural product scientists have turned to nature
for assistance to eradicate this dreadful disease. Natural products can
have potential therapeutic use for the emerging diseases and also enable
to eliminate them, it has been reported that 234 drugs for various
diseases have been isolated and were approved from natural products for
treating various diseases during the timeline of 1981 to 2014. About
antiviral 64 small molecules and 138 antiviral drugs have been approved
from the same time period \textsuperscript{6}. Mushrooms belong to the
separate Kingdom of Fungi and Phylum Basidiomycota. They are also an
excellent source of natural products and antivirals which expresses
antiviral activity in both enveloped and non-enveloped RNA viruses by
mechanisms which can prohibit the attachment and entry, replication,
assembly and release of the same. Such antiviral activity is possible
through compounds which are in different forms of like analogues,
derivatives, fraction or direct polysaccharides, triterpenoids,
proteoglycan, proteins, lectins, polyphenols and
enzymes\textsuperscript{7}. A recent study involving \emph{in silico}
approach for Main Protease (MPro) inhibition through 36 compounds with
edible and medicinal mushrooms with anti-HIV activity
\textsuperscript{8} but they fail to investigate and recognize compounds
with wide antiviral activity especially in the light of compounds which
prohibit or totally eradicate the upper respiratory viruses, they are
only single targeted and they are not validated by molecular dynamics
which predicts the stability of the docked molecule.

In this study our focus is on edible mushrooms which accessible in super
markets such as \emph{Lentinula edodes} , \emph{Agaricus bisporus}
,\emph{Pleutorus ostreatus} and \emph{Hericium erinaceus} . And we
target their main compounds such as Eritadenine, Gallic acid, Pleuran
and Ergosterol peroxide, these main compounds were chosen especially due
to their ability to inhibit upper respiratory infections which are
specifically caused by viruses from known existing literature. According
to the literature, Eritadenine is a main compound of \emph{L. edodes}and
has been synthesized synthetically and was found to have antiviral
activity against Poxviruses, Paramyxovirus, Rhabdovirus and
Reovirus\textsuperscript{9, 10}. \emph{A. bisporus} has Gallic acid as
its main component was reported to have activity against early viral
entry of hepatitis C, Herpes Simplex Virus-1 (HSV-1), Human
Immunodeficiency Virus-1 (HIV-1) and Influenza-A virus
\textsuperscript{11}. Pleuran a main compound of \emph{P. ostreatus} was
studied to have activity against Influenza --A virus, provided cellular
immune response and respiratory tract infections in athletes
\textsuperscript{12, 13, 14}. Ergosterol Peroxide a main component from
\emph{H. erinaceus} was examined to have antiviral activity against
porcine delta coronavirus and other upper respiratory infections
\textsuperscript{15, 16, 17}.

Due to these molecules has such antiviral activities, we target them
against the Main Protease (Mpro) and the spike protein (S) of the
SARS-CoV-2 virus in order to inhibit these targets and prohibit the
entry and replication of the virus within the cell by using molecular
docking tools and molecular dynamics simulation studies. We have also
undertaken studies to assess the target accuracy and pharmacokinetic
parameters by \emph{in silico} analysis and compare them to the existing
antivirals proposed against the SARS-CoV-2 with the targets mentioned in
the literature.

\textbf{2. MATERIALS AND METHODS:}

2.1 DOCKING OF ERITADENINE, GALLIC ACID, ERGOSTEROL PEROXIDE AND PLEURAN
ON SARS-COV-2 MAIN PROTEASE AND SPIKE PROTEIN:

2.1.1 LIGAND PREPARATION:

The ligands of interest Eritadenine (PubChem CID 159961), Gallic Acid
(PubChem CID 370), Ergosterol (PubChem CID 5351516) were obtained from
PubChem database \textsuperscript{18}. Pleuran was designed using
Glycam-Web webserver \textsuperscript{19}. Molecules in 2D formats were
converted to 3D mol2 format and protonated using
OpenBabel\textsuperscript{20}.

2.1.2 RECEPTOR PREPARTION:

3D crystal structure of SARS-CoV-2 Main protease (PDB ID: 6LU7) and
SARS-CoV-2 Spike protein (PDB ID: 6YOR) were obtained from RCSB PDB
database \textsuperscript{21}. Protein chains with appropriate chain
identifiers for the protein were selected and retained other ligands
present in the molecule were removed. Webservers
3DLigandSite\textsuperscript{22} and RaptorX binding
\textsuperscript{23} was used to identify the active site in the protein
given in the figure 1. The protein receptor was processed using the Dock
Prep module of UCSF Chimera using AMBER parm99 partial charges.

2.1.3 DOCKING PARAMETERS:

All docking calculations were performed using Dock6 version (6.6).
Active sites were identified and prepared by selecting spheres at a
distance of 1--5 \selectlanguage{ngerman}Å from the binding regions. Grid boxes with 5 Å and 15
Å margins were generated around the selected spheres for small and large
ligands respectively. A standard flexible docking protocol with the
maximum number of anchor orientations attempted was set to 1,000 and all
100,000 orientations was employed to sample internal degrees of freedom
of the ligands. Grid scoring based on the intermolecular non-bonded
terms (viz. van der Waals for steric and electrostatic interactions) was
computed using AMBER force field ff99 to identify the best orientation
of each ligand. Finally, the best-scored conformer was retained for
scrutiny and further refinement and Amber-based scoring. All protein
ligand interactions were detected and visualized using by the PLIP
webserver \textsuperscript{24} and LigPlot \textsuperscript{25}.

2.2 MOLECULAR DYNAMICS OF ERITADENINE, GALLIC ACID, ERGOSTEROL PEROXIDE
AND PLEURAN ON SARS-COV-2 MAIN PROTEASE AND SPIKE PROTEIN:

The docked structures were used for molecular dynamics simulations using
AMBER force field and TIP3P water model in GROMACS 2019. The parameters
for docked ligands were prepared using Acypype. A vacuum energy
minimization step was performed by employing the steepest descent
algorithm for 50,000 steps and conjugate gradient minimization was
performed for 5000 steps. Sodium (Na+) and chloride (Cl-) counter ions
were added at a physiological concentration and the boundaries of the
dodecahedron box were adjusted to 10Å in a unit cell. The complexes were
again subjected to energy minimization for 50,000 steps for
stabilization. Position restraint and unrestrained dynamics simulations
and Parrinello- Rahman pressure- coupling bath was used for
equilibration step of the system at temperature 300K using a Nose-Hoover
thermostat under pressure of 1 atm for 100 ps. For simulations, all
bonds were constrained using the LINCS algorithm. The Particle- Mesh
Ewald method was used for electrostatic calculations by maintaining a
cut-off distance of 1.4nm for coulomb and Van der Waals interactions,
and finally, the production run for 10 ns was performed. GROMACS
built-in functions were utilized to calculate RMSD, RMSF and Hydrogen
bonds. Excel was used to produce graphs of the results.

2.3 ADME PREDICTION:

The prediction of Adsorption, Distribution, Metabolism and Excretion was
done by obtaining the Simplified Molecular-Input Line-Entry System
(SMILES) format of the ligands Eritadenine, Gallic acid, Ergosterol
peroxide and Pleuran was taken from PubChem database and was provided as
an input to the SWISS-ADMET website which analyses the lipophilicity,
water solubility, druglikeness and medicinal chemistry of the compound
submitted \textsuperscript{26}.

2.4 TARGET PREDICTION:

The target prediction of the compounds Eritadenine, Gallic acid,
Ergosterol peroxide and Pleuran was analyzed by entering the SMILES and
by choosing the \emph{Homo sapiens} button to the Swiss target
prediction website which in turn provides info about possible side
effects or cross reactivity caused due to the effect of molecules in the
physiological or genetic effect in the organs of the human
body\textsuperscript{27}.

2.5 TOXICITY PREDICTION:

The toxicity of the ligands eritadenine, gallic acid, ergosterol
peroxide and pleuran was analyzed by incorporating the SMILES data of
these compounds from PubChem database to the ADMET Lab2.0 website and
Toxicity option was selected and analyzed. ADMET Lab2.0 examines the
ligand's toxicity among systemic organs in the human body, TOX21 Pathway
and Toxicophore property rules ranging from acute toxicity, genotoxic
carcinogenicity, non- genotoxic carcinogenicity, skin sensitization,
aquatic toxicity, non-biodegradability and sureChEMBL
Rule\textsuperscript{28}.

\textbf{3. RESULTS:}

3.1 DOCKING:

The docking analysis of the compounds docked with Mpro and spike protein
of SARS-CoV-2 yielded negative values for free energy respectively they
were as follows. The grid box expressed negative values for free
energies observed in Mpro they are -1.068 KJ/mol was observed for
Eritadenine, -3.167 KJ/mol for Gallic acid, -0.420 KJ/mol for Ergosterol
peroxide and -5.035 KJ/mol for Pleuran. Similarly, the values of free
energies observed in Spike Protein were -0.783 KJ/mol, -2.140 KJ/mol,
1.027 KJ/mol and -5.241 KJ/mol respectively for the above four
compounds. The binding confirmations of the docked protein of Mpro are
hydrogen bonds and salt bridge formation for Eritadenine, hydrogen bonds
were formed in Gallic acid, hydrogen bond and hydrophobic interactions
were developed in Ergosterol peroxide and hydrogen bonds were formed
with the molecule of Pleuran. Correspondingly, the binding confirmations
of the docked protein of spike protein are hydrogen bonds were formed in
the ligands of eritadenine, gallic acid and pleuran; the hydrogen bonds
and hydrophobic interactions are developed in the compound Ergosterol
peroxide.

3.1.1 ERITADENINE:

3.1.1.1 DOCKED POSE AND PROTEIN LIGAND INTERACTION:

The docked pose of the ligand eritadenine along with protein ligand
interaction is given in the figures 2a, 2a1, 2b and 2b1. And protein
ligand interactions are tabulated in Table-1.

3.1.2 GALLIC ACID:

3.1.2.1 DOCKED POSE AND PROTEIN LIGAND INTERACTION:

The docked pose of the ligand gallic acid along with protein ligand
interaction is given in the figure 2c, 2c1, 2d and 2d1. And protein
ligand interactions are tabulated in Table-2.

3.1.3 ERGOSTEROL PEROXIDE:

3.1.3.1 DOCKED POSE AND PROTEIN LIGAND INTERACTION:

The docked pose of the ligand ergosterol peroxide along with protein
ligand interaction is given in the figure 2e, 2e1, 2f and 2f1. And
protein ligand interactions are tabulated in Table-3.

3.1.4 PLEURAN

3.1.4.1 DOCKED POSE AND PROTEIN LIGAND INTERACTION:

The docked pose of the ligand pleuran along with protein ligand
interaction is given in the figure 2g, 2g1, 2h and 2h1. And protein
ligand interactions are tabulated in Table-4.

3.2 MOLECULAR DYNAMICS:

3.2.1 ROOT MEAN SQUARE DEVIATION (RMSD) AND ROOT MEAN SQUARE FLUCTUATION
(RMSF):

The RMSD, RMSF produced from the docked compounds with targets Main
Protease (MPro) and Spike Protein (S) are given as Figure 3a, 3b, 4a and
4b as follows:

3.2.2 HYDROGEN BONDING:

The hydrogen bonding which was formed during the molecular dynamics
simulation was tabulated in Tables 5, 6, 7 and 8 for the ligand-protein
bound complexes of Main Protease (MPro) and in Tables 9, 10, 11, and 12
for the docked complexes of Spike Protein (S).

3.3 ADME PREDICTION:

3.3.1 ERITADENINE:

The results which appeared after the submission of Eritadenine molecule
in the SWISS-ADME database showed that the molecule, Eritadenine 18
heavy atoms, 7 hydrogen bond acceptors, 4 hydrogen bond donors and
147.38 Å\textsuperscript{2} of Topological Polar Surface Area (TPSA).
The lipophilicity parameters are optimal in nature. The estimated
solubility of Eritadenine is -0.36 which points it to be in the very
soluble class, \emph{in silico} prediction of aqueous solubility with
response to TPSA is about -0.75 which categorizes to very soluble class
as well, water solubility by fragmental method puts the compound to very
soluble class with assigning the value of -0.29. The pharmacokinetics
properties determined that Eritadenine has low gastrointestinal
absorption, non-blood brain barrier permeant, does not act as P-gp
substrate and does not inhibit factors such as CYP1A2, CYP2C19, CYP2C9,
CYP2D6 and CYP3A4. The molecule is skin permeable with log Kp rate about
-9.14cm/s. And the molecule obeys Lipinski's rule of five and Muegge
rules of druglikeness and also obeys Pan-Assay Interference Compounds
(PAINS), Brenk, Leadlikeness rules of medicinal chemistry.

3.3.2 GALLIC ACID:

The results of Gallic acid contains 12 heavy atoms, 5 hydrogen bond
acceptors, 4 hydrogen bond donors and TPSA is found to be 97.99
Å\textsuperscript{2}. The lipophilicity parameters were very optimal for
the ligand. And water solubility parameters were soluble in nature as
predicted values are -1.64, -2.34 and -0.04 with respect to estimated
solubility (Log S-ESOL), \emph{in silico} prediction of solubility with
reference to TPSA (Log S- Ali) and water solubility by fragmental method
(Log S- SILICOS-IT) which gives an inference of very soluble, soluble
and soluble classes according to the values projected. Estimated
pharmacokinetic data projects that the Gallic acid is highly absorbable
gastrointestinally, non- blood brain barrier permeant, non-P-gp
substrate, does not inhibit potential cytochrome P450 enzymes as
mentioned above, also has skin permeability rate of -6.84 cm/s. And the
compound obeys druglikeness rules such as Lipinski's, Veber and Egan.
But the molecule doesn't obey any rules of medicinal chemistry.

3.3.3 ERGOSTEROL PEROXIDE:

The ligand Ergosterol peroxide has 31 heavy atoms, 3 hydrogen bond
acceptors and 1 hydrogen bond donor and TPSA is about 38.69
Å\textsuperscript{2}. They are highly lipophilic in nature. The water
solubility parameters are with predicted values of -6.46 for Log S- ESOL
which is poorly soluble, -7.33 for Log S-Ali which is poorly soluble and
-4.51 for Log S- SILICOS-IT which is moderately soluble. The
pharmacokinetic estimated data exclaims that the molecule is highly
absorbable gastrointestinally, non- blood brain barrier permeant,
non-P-gp substrate, does not inhibit potential cytochrome P450 enzymes
such as CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. It also has skin
permeability rate of -4.15 cm/s. Ergosterol peroxide obeys druglikeness
rules of Lipinski and Veber. There's no PAINS violation in medicinal
chemistry rules.

3.3.4 PLEURAN:

Pleuran has 41 hydrogen bond acceptors, 26 hydrogen bond donors and it
has TPSA about 664.43 Å\textsuperscript{2}. They are highly lipophilic
and less hydrophilic in nature. The pharmacokinetic data shows that the
molecule is a non P-gp substrate, highly absorbable gastrointestinally,
non- blood brain barrier permeant and does not inhibit potential
cytochrome P450 enzymes such as CYP1A2, CYP2C19, CYP2C9, CYP2D6 and
CYP3A4. The molecule obeys PAINS and Brenk medicinal chemistry rules.

3.4 TARGET PREDICTION:

After the analysis the target prediction of the ligands Eritadenine,
Gallic acid, Ergosterol peroxide and Pleuran were given accordingly as
the pie charts for top 15 hits for Eritadenine, all estimates for Gallic
acid, top 15 hits for Ergosterol peroxide and all estimates for Pleuran
(Figures 10-13) and the respective log output table with known protein
complexes are given along with probability score with each binding to
estimated protein complexes, the output table of results for the
compounds are given in the supplementary file. As projected by the
output file the compounds may reach the target with high accuracy to
which it is targeted to. Whereas the target activities of Eritadenine,
Gallic acid, Ergosterol peroxide and Pleuran are sought in literature
and their validation is discussed in the discussion section to provide
the fact of target accuracy.

3.5 TOXICITY PREDICTION:

3.5.1 SYSTEMIC TOXICITY:

The systemic toxicity properties of the ligands eritadenine, gallic
acid, ergosterol peroxide and pleuran are tabulated in Table-13.

3.5.2 TOX21 PATHWAY:

The properties of the ligands which are studied for TOX21 pathway are
given in the Table-14 as follows:

3.5.3 TOXICOPHORE RULES:

The toxicophore rules of the ligands of interest are tabulated in
Table-15.

\textbf{4. DISCUSSION:}

Mushrooms are found to possess antiviral activity also they are reviewed
to have therapeutic effect against inflammation and pneumonic
superinfection against recent global pandemic of
COVID-19\textsuperscript{29}. We focused on the edible mushrooms which
are commonly available in the markets rather than deep search in the
forest and examined the main compounds which has broad activity against
upper respiratory viruses via literature review and found out four
compounds fall into the above categories mentioned. And targets Main
Protease (Mpro) and Spike Protein were chosen to see the inhibitory
effect of the ligands on the pre-entry stage and protein cleavage stage
in the life cycle of the SARS-CoV-2 virus leading to disruption and
decrease of the viral load \emph{in vivo} . And also due to recent
outbreak of different variants, whose mutation took place in the spike
protein of the SARS-CoV-2 virus, thankfully they carry similar
inhibition sites and the most mutation took place in the furin loops and
so the spike protein was chosen as the target of interest
\textsuperscript{30}.

The ligands were successfully docked against inhibition site of Main
Protease with following docking scores -1.068 Kcal/ mol for Eritadenine,
-3.617 Kcal/ mol for Gallic Acid, -0.420 Kcal/ mol for Ergosterol
Peroxide and -5.035 Kcal/ mol for Pleuran respectively. Similarly, the
ligands also docked successfully against Spike Protein with docking
scores such as -0.783 Kcal/ mol for Eritadenine, -2.140 Kcal/ mol for
Gallic Acid, 1.027 Kcal/ mol for Ergosterol Peroxide and -5.241 Kcal/
mol for Pleuran respectively. And the docked complexes exhibited
convergence within 10 ns of molecular dynamics whose RMSD values ranged
from 1Å to 2.5Å for all ligands which has been bound to Main protease
and RMSF values ranged from 5Å to 6.5Å. Similarly, RMSD values ranged
from 1Å to 2Å and also the RMSF values ranged from 0.5Å to 3.5Å
respectively in the Spike Protein target, therefore all protein ligand
complexes are stable in both targets according to results in RMSD
analysis as well as in RMSF analysis. All complexes expressed strong
hydrogen bonding throughout the time of molecular dynamics simulation
through which it gives an inference that the protein ligand complexes
are stable \textsuperscript{31}. All other compounds except pleuran did
express good druggability properties during \emph{in silico} ADME
analysis. Similarly, during target analysis the compounds except pleuran
showed good targeting against protease enzymes. But in literature
pleuran has been found to express good activity against protease enzymes
and also effective in progressivity towards being a drug and also has
immunomodulatory effect \textsuperscript{32}. Based on toxicity all
ligands expressed minimum toxicity levels except eritadenine but are
mostly non-toxic to the important organs such as liver, heart and
kidneys based on the simulation projected in the results.

When comparing these compounds with already repurposed drugs such as
Lopinavir , Famciclovir, Drunavir, Amprenavir and N3 whose docking
scores are -9.918 Kcal/ mol, -7.546 Kcal/ mol, -7.505 Kcal/ mol, -8.655
Kcal/ mol, -7.5 Kcal/ mol respectively. And the repurposed drugs which
are mentioned above exhibit higher docking score than the compounds of
interest \textsuperscript{33, 34}. The ligand of interest has lesser
docking score and has more significance. Therefore the compounds which
were studied can be used for therapeutic purposes against COVID-19. We
the authors also propose as the inhibition site of all spike proteins in
variants of concern are similar, one particular drug or a compound which
has been studied to have inhibitory effect can be used to treat
SARS-CoV-2.

\textbf{5. CONCLUSION:}

The small compound eritadenine has exhibited excellent properties
against all aforementioned categories of target, toxicity and ADME so it
could be propagated as a drug to combat the SARS-CoV-2. Whereas the
other compounds also possessed such immunomodulatory properties as
mentioned in the existing literature mentioned above. However, this work
is foundational, but the results are promising and further studies of
these ligands \emph{in vitro} and \emph{in vivo} should be studied to
decipher the therapeutic role of these compounds.

\textbf{6. REFERENCES:}

\textsuperscript{1} Wu C, Liu Y, Yang Y, Zhang P, Zhong W, Wang Y, Wang
Q, Xu Y, Li M, Li X, Zheng M, Chen L, Li H. Analysis of therapeutic
targets for SARS-CoV-2 and discovery of potential drugs by computational
methods. Acta Pharm Sin. B 2020;10(5):766-788. Doi:
10.1016/j.apsb.2020.02.008.

\textsuperscript{2} V'kovski P, Kratzel A, Steiner S, Stalder H, Thiel
V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat
Rev Microbiol. 2021; 19(3): 155-170. Doi: 10.1038/s41579-020-00468-6.

\textsuperscript{3} COVID-19 Coronavirus Pandemic. 2021. Available at
https://www.worldometers.info/coronavirus/ {[}Accessed at August 16,
2021{]}.

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\textbf{7. TABLES:}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Compound\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Protein\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
No of H Bonds\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Residue Receptor\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Ligand\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Bond Length (\selectlanguage{ngerman}Å)\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Docking Score (Kcal/ mol)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Eritadenine\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Mpro\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Gly 143 (H) His 164 (H) His 41 (H)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N2 O2 O2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3.05 2.85 4.39\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-1.068 -1.068 -1.068\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Spike\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Asn 343 (H) Asn 343 (H) Val 367 (H) Ser 371 (H) Trp 436 (H)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
O.co2 O2 O2 O3 N2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3.03 2.43 3.23 3.32 3.45\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-0.783 -0.783 -0.783 -0.783 -0.783\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table-1. Interaction of SARS-CoV-2 Mpro and Spike Protein with
Eritadenine Ligand.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Compound\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Protein\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
No of H Bonds\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Residue Receptor\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Ligand\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Bond Length (\selectlanguage{ngerman}Å)\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Docking Score (Kcal/ mol)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Gallic Acid\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Mpro\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
7\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Leu 141 (H) Leu 141 (H) Gly 143 (H) Ser 144 (H) Cys 145 (H) Glu 166 (H)
Gln 189 (H)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
O2 O2 O2 O2 O2 O.co2 O2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2.12 1.92 3.11 2.4 2.81 2.23 2.69\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-3.617 -3.617 -3.617 -3.617 -3.617 -3.617 -3.617\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Spike\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Asn 343 (H) Asn 343 (H) Ser 371 (H) Phe 343 (H)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
O2 O2 O.co2 O2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2.33 2.06 2.44 3.36\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-2.140 -2.140 -2.140 -2.140\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table-2. Interaction of SARS-CoV-2 Mpro and Spike Protein with Gallic
Acid Ligand.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Compound\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Protein\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
No of H Bonds\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Residue Receptor\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Ligand\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Bond Length (\selectlanguage{ngerman}Å)\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Docking Score (Kcal/ mol)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ergosterol Peroxide\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Mpro\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Asn 142 (H) Glu 166 (H)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
O3 O2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3.22 3.68\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-0.420 -0.420\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Spike\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ser 373 (H) Val 367 (H) Asn 370 (H) Phe 374 (H)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
O3 O2 O2 O2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2.71 3.83 3.96 3.96\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.027 1.027 1.027 1.027\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table-3. Interaction of SARS-CoV-2 Mpro and Spike Protein with
Ergosterol Peroxide Ligand.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Compound\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Protein\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
No of H Bonds\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Residue Receptor\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Ligand\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Bond Length (\selectlanguage{ngerman}Å)\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Docking Score (Kcal/ mol)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Pleuran\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Mpro\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Pro 168 (H) Thr 169 (H) Thr 26 (H) Thr 26 (H) Gly 138 (H) Gly 170 (H)
Arg 188 (H) Gln 189 (H) Glu 166 (H) Glu 166 (H) His 41 (H) His 142
(H)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
O2 O2 O3 O2 O2 O2 O2 O3 O2 O3 O2 O2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3.47 2.98 3.1 2.47 3.51 2.95 2.72 3.15 2.37 2.26 4.85 5.30\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-5.035 -5.035 -5.035 -5.035 -5.035 -5.035 -5.035 -5.035 -5.035 -5.035
-5.035 -5.035\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Spike\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
19\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Thr 376 (H) Thr 376 (H) Thr 376 (H) Gly 404 (H) Arg 408 (H) Arg 408 (H)
Arg 408 (H) Asn 343 (H) Ser 373 (H) Ser 375 (H) Tyr 508 (H) Tyr 508 (H)
Trp 436 (H) Asn 440 (H) Ala 372 (H) Asn 349 (H) Ser 375 (H) Ser 373 (H)
Asn 440 (H)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
O3 O3 O3 O2 O3 O3 O3 O3 O2 O3 O3 O3 N2 O3 O2 O3 O2 O2 O2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2.13 2 2.14 2.88 2.74 2.73 2.83 2.87 3.15 3.17 1.92 1.91 2.9 2.83 2.65
2.54 3.13 2.58 1.92\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-5.241 -5.241 -5.241 -5.241 -5.241 -5.241 -5.241 -5.241 -5.241 -5.241
-5.241 -5.241 -5.241 -5.241 -5.241 -5.241 -5.241 -5.241 -5.241\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table-4. Interaction of SARS-CoV-2 Mpro and Spike Protein with Pleuran
Ligand.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Donor} & \textbf{Hydrogen} & \textbf{Acceptor} & \textbf{\%
Existence}\tabularnewline
\midrule
\endhead
UNK307O11 & UNK307H24 & ASP187O & 98.402\tabularnewline
UNK307N7 & UNK307H18 & HIS164O & 52.647\tabularnewline
GLN189NE2 & GLN189HE21 & UNK307O15 & 6.693\tabularnewline
HIS41NE2 & HIS41HE2 & UNK307N7 & 3.297\tabularnewline
\bottomrule
\end{longtable}

Table-5. Dominant Hydrogen Bond Donors and Acceptors in MD Simulation
Between Mpro and Eritadenine of SARS-CoV-2.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Donor} & \textbf{Hydrogen} & \textbf{Acceptor} & \textbf{\%
Existence}\tabularnewline
\midrule
\endhead
LIG307O1 & LIG307H3 & HIS164O & 50.05\tabularnewline
HIS163NE2 & HIS163HE2 & LIG307O2 & 44.356\tabularnewline
LIG307O & LIG307H2 & SER144OG & 36.863\tabularnewline
HIS163NE2 & HIS163HE2 & LIG307O & 24.975\tabularnewline
GLU166N & GLU166H & LIG307O3 & 10.49\tabularnewline
GLY143N & GLY143H & LIG307O1 & 9.59\tabularnewline
LIG307O & LIG307H2 & HIS164O & 8.691\tabularnewline
LIG307O2 & LIG307H4 & PHE140O & 3.596\tabularnewline
SER144N & SER144H & LIG307O & 3.397\tabularnewline
ASN142ND2 & ASN142HD21 & LIG307O4 & 3.297\tabularnewline
ASN142ND2 & ASN142HD21 & LIG307O3 & 2.098\tabularnewline
LIG307O2 & LIG307H4 & GLU166OE2 & 1.798\tabularnewline
GLU166N & GLU166H & LIG307O4 & 1.099\tabularnewline
LIG307O & LIG307H2 & LEU141O & 1.099\tabularnewline
\bottomrule
\end{longtable}

Table-6. Dominant Hydrogen Bond Donors and Acceptors In MD Simulation
Between Mpro and Gallic Acid of SARS-CoV-2.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Donor} & \textbf{Hydrogen} & \textbf{Acceptor} & \textbf{\%
Existence}\tabularnewline
\midrule
\endhead
SER46N & SER46H & LIG307O & 27.373\tabularnewline
SER46N & SER46H & LIG307O1 & 14.985\tabularnewline
THR45OG1 & THR45HG1 & LIG307O2 & 7.293\tabularnewline
THR45OG1 & THR45HG1 & LIG307O1 & 5.095\tabularnewline
SER46OG & SER46HG & LIG307O1 & 3.996\tabularnewline
SER46OG & SER46HG & LIG307O & 3.197\tabularnewline
THR45OG1 & THR45HG1 & LIG307O & 1.099\tabularnewline
\bottomrule
\end{longtable}

Table-7. Dominant Hydrogen Bond Donors and Acceptors In MD Simulation
Between Mpro and Ergosterol Peroxide of SARS-CoV-2.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Donor} & \textbf{Hydrogen} & \textbf{Acceptor} & \textbf{\%
Existence}\tabularnewline
\midrule
\endhead
GLU166N & GLU166H & LIG307O7 & 46.254\tabularnewline
LIG307O27 & LIG307H74 & THR26O & 34.965\tabularnewline
LIG307O37 & LIG307H6O & GLU166OE1 & 30.969\tabularnewline
GLU166N & GLU166H & LIG307O14 & 29.271\tabularnewline
GLY143N & GLY143H & LIG307O41 & 28.472\tabularnewline
GLN192N & GLN192H & LIG307O2 & 26.873\tabularnewline
LIG307O26 & LIG307H73 & HIS41NE2 & 23.576\tabularnewline
LIG307O41 & LIG307H78 & ASN142OD1 & 20.579\tabularnewline
CYS145N & CYS145H & LIG307O41 & 19.081\tabularnewline
LIG307O37 & LIG307H6O & PHE140O & 17.283\tabularnewline
GLN189NE2 & GLN189HE21 & LIG307O26 & 17.083\tabularnewline
LIG307O2 & LIG307H2O & GLN192O & 15.984\tabularnewline
LIG307O1 & LIG307HO1 & GLN192O & 15.185\tabularnewline
GLN192N & GLN192H & LIG307O1 & 14.585\tabularnewline
LIG307O11 & LIG307H46 & PRO168O & 14.585\tabularnewline
LIG307O38 & LIG307H75 & GLY170O & 13.686\tabularnewline
LIG307O9 & LIG307H44 & GLU166OE1 & 13.287\tabularnewline
PHE140N & PHE140H & LIG307O38 & 11.688\tabularnewline
LIG307O40 & LIG307H77 & HIS164O & 10.789\tabularnewline
HIS41NE2 & HIS41HE2 & LIG307O19 & 10.49\tabularnewline
HIS172NE2 & HIS172HE2 & LIG307O37 & 10.19\tabularnewline
LIG307O38 & LIG307H75 & PHE140O & 10.09\tabularnewline
LIG307O21 & LIG307H68 & ASN142OD1 & 7.093\tabularnewline
LIG307O7 & LIG307H42 & GLU166O & 6.593\tabularnewline
LIG307O10 & LIG307H45 & PRO168O & 6.494\tabularnewline
HIS41NE2 & HIS41HE2 & LIG307O13 & 6.094\tabularnewline
LIG307O37 & LIG307H6O & GLU166OE2 & 4.995\tabularnewline
LIG307O26 & LIG307H73 & HIS41ND1 & 4.695\tabularnewline
LIG307O40 & LIG307H77 & ARG188O & 4.296\tabularnewline
LIG307O25 & LIG307H72 & PRO168O & 4.096\tabularnewline
LIG307O4 & LIG307H4O & GLN189O & 3.796\tabularnewline
LIG307O21 & LIG307H68 & GLU166OE2 & 3.696\tabularnewline
LIG307O11 & LIG307H46 & THR169O & 3.596\tabularnewline
LIG307O39 & LIG307H76 & GLY170O & 3.197\tabularnewline
GLN189NE2 & GLN189HE21 & LIG307O6 & 3.097\tabularnewline
ASN142ND2 & ASN142HD21 & LIG307O41 & 2.797\tabularnewline
GLN189NE2 & GLN189HE21 & LIG307O4 & 2.597\tabularnewline
LIG307O3 & LIG307H3O & GLN189O & 2.398\tabularnewline
LIG307O38 & LIG307H75 & THR169O & 2.398\tabularnewline
LIG307O1 & LIG307HO1 & GLU166O & 2.298\tabularnewline
LIG307O23 & LIG307H70 & PHE140O & 2.298\tabularnewline
ASN142ND2 & ASN142HD21 & LIG307O22 & 2.198\tabularnewline
LIG307O15 & LIG307H49 & ASN142OD1 & 2.198\tabularnewline
LIG307O13 & LIG307H48 & THR26O & 1.998\tabularnewline
THR26N & THR26H & LIG307O20 & 1.898\tabularnewline
GLN189NE2 & GLN189HE21 & LIG307O40 & 1.898\tabularnewline
LIG307O38 & LIG307H75 & GLU166OE1 & 1.898\tabularnewline
GLY143N & GLY143H & LIG307O27 & 1.798\tabularnewline
LIG307O22 & LIG307H69 & ASN142OD1 & 1.798\tabularnewline
LYS137NZ & LYS137HZ1 & LIG307O25 & 1.698\tabularnewline
ASN142ND2 & ASN142HD21 & LIG307O37 & 1.698\tabularnewline
LIG307O1 & LIG307HO1 & GLN189O & 1.598\tabularnewline
LIG307O39 & LIG307H76 & PRO168O & 1.598\tabularnewline
ASN142ND2 & ASN142HD21 & LIG307O15 & 1.499\tabularnewline
ASN142ND2 & ASN142HD21 & LIG307O27 & 1.399\tabularnewline
LIG307O20 & LIG307H51 & THR26O & 1.399\tabularnewline
ASN142ND2 & ASN142HD21 & LIG307O8 & 1.299\tabularnewline
LIG307O4 & LIG307H4O & GLN189OE1 & 1.199\tabularnewline
LIG307O18 & LIG307H50 & THR169O & 1.099\tabularnewline
LIG307O41 & LIG307H78 & ASN119OD1 & 1.099\tabularnewline
\bottomrule
\end{longtable}

Table-8. Dominant Hydrogen Bond Donors and Acceptors In MD Simulation
Between Mpro and Pleuran of SARS-CoV-2.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Donor} & \textbf{Hydrogen} & \textbf{Acceptor} & \textbf{\%
Existence}\tabularnewline
\midrule
\endhead
UNK529N7 & UNK529H18 & VAL367O & 14.885\tabularnewline
ASN343ND2 & ASN343HD21 & UNK529O15 & 8.591\tabularnewline
UNK529N7 & UNK529H18 & PHE342O & 8.192\tabularnewline
PHE338N & PHE338H & UNK529N1 & 7.892\tabularnewline
UNK529N7 & UNK529H18 & ASN343OD1 & 7.892\tabularnewline
ASN343ND2 & ASN343HD21 & UNK529N3 & 7.193\tabularnewline
SER373OG & SER373HG & UNK529N7 & 7.093\tabularnewline
UNK529O15 & UNK529H26 & ASN343OD1 & 6.793\tabularnewline
ASN343ND2 & ASN343HD21 & UNK529O11 & 5.894\tabularnewline
ASN343ND2 & ASN343HD21 & UNK529N1 & 3.596\tabularnewline
SER373OG & SER373HG & UNK529N1 & 3.596\tabularnewline
UNK529O11 & UNK529H24 & ASN343OD1 & 3.397\tabularnewline
TRP436NE1 & TRP436HE1 & UNK529N7 & 2.597\tabularnewline
PHE338N & PHE338H & UNK529N7 & 2.298\tabularnewline
SER371OG & SER371HG & UNK529O13 & 2.098\tabularnewline
ASN343ND2 & ASN343HD21 & UNK529N7 & 1.998\tabularnewline
SER371OG & SER371HG & UNK529O14 & 1.798\tabularnewline
SER373OG & SER373HG & UNK529O13 & 1.499\tabularnewline
SER373OG & SER373HG & UNK529O14 & 1.499\tabularnewline
UNK529O11 & UNK529H24 & SER373O & 1.299\tabularnewline
\bottomrule
\end{longtable}

Table-9. Dominant Hydrogen Bond Donors and Acceptors In MD Simulation
Between Spike Protein and Eritadenine of SARS-CoV-2.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Donor} & \textbf{Hydrogen} & \textbf{Acceptor} & \textbf{\%
Existence}\tabularnewline
\midrule
\endhead
UNK529N7 & UNK529H18 & VAL367O & 14.885\tabularnewline
ASN343ND2 & ASN343HD21 & UNK529O15 & 8.591\tabularnewline
UNK529N7 & UNK529H18 & PHE342O & 8.192\tabularnewline
PHE338N & PHE338H & UNK529N1 & 7.892\tabularnewline
UNK529N7 & UNK529H18 & ASN343OD1 & 7.892\tabularnewline
ASN343ND2 & ASN343HD21 & UNK529N3 & 7.193\tabularnewline
SER373OG & SER373HG & UNK529N7 & 7.093\tabularnewline
UNK529O15 & UNK529H26 & ASN343OD1 & 6.793\tabularnewline
ASN343ND2 & ASN343HD21 & UNK529O11 & 5.894\tabularnewline
ASN343ND2 & ASN343HD21 & UNK529N1 & 3.596\tabularnewline
SER373OG & SER373HG & UNK529N1 & 3.596\tabularnewline
UNK529O11 & UNK529H24 & ASN343OD1 & 3.397\tabularnewline
TRP436NE1 & TRP436HE1 & UNK529N7 & 2.597\tabularnewline
PHE338N & PHE338H & UNK529N7 & 2.298\tabularnewline
SER371OG & SER371HG & UNK529O13 & 2.098\tabularnewline
ASN343ND2 & ASN343HD21 & UNK529N7 & 1.998\tabularnewline
SER371OG & SER371HG & UNK529O14 & 1.798\tabularnewline
SER373OG & SER373HG & UNK529O13 & 1.499\tabularnewline
SER373OG & SER373HG & UNK529O14 & 1.499\tabularnewline
UNK529O11 & UNK529H24 & SER373O & 1.299\tabularnewline
\bottomrule
\end{longtable}

Table-10. Dominant Hydrogen Bond Donors and Acceptors In MD Simulation
Between Spike Protein and Gallic Acid of SARS-CoV-2.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Donor} & \textbf{Hydrogen} & \textbf{Acceptor} & \textbf{\%
Existence}\tabularnewline
\midrule
\endhead
SER373OG & SER373HG & LIG529O1 & 51.948\tabularnewline
SER373OG & SER373HG & LIG529O & 51.349\tabularnewline
SER371OG & SER371HG & LIG529O & 8.092\tabularnewline
SER373OG & SER373HG & LIG529O2 & 4.396\tabularnewline
SER371OG & SER371HG & LIG529O1 & 2.597\tabularnewline
\bottomrule
\end{longtable}

Table-11. Dominant Hydrogen Bond Donors and Acceptors In MD Simulation
Between Spike Protein and Ergosterol Peroxide of SARS-CoV-2.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Donor} & \textbf{Hydrogen} & \textbf{Acceptor} & \textbf{\%
Existence}\tabularnewline
\midrule
\endhead
SER375OG & SER375HG & LIG529O5 & 91.309\tabularnewline
THR376OG1 & THR376HG1 & LIG529O11 & 81.419\tabularnewline
LIG529O4 & LIG529H4O & ALA372O & 76.723\tabularnewline
LIG529O8 & LIG529H43 & GLN506OE1 & 71.628\tabularnewline
LIG529O12 & LIG529H47 & ASN437O & 71.429\tabularnewline
TRP436NE1 & TRP436HE1 & LIG529O13 & 66.234\tabularnewline
LIG529O20 & LIG529H51 & PHE342O & 64.635\tabularnewline
ARG509NH1 & ARG509HH11 & LIG529O20 & 62.637\tabularnewline
LIG529O27 & LIG529H74 & ALA344O & 48.152\tabularnewline
LIG529O39 & LIG529H76 & GLY404O & 45.654\tabularnewline
LYS378NZ & LYS378HZ1 & LIG529O18 & 34.466\tabularnewline
GLN506NE2 & GLN506HE21 & LIG529O15 & 17.582\tabularnewline
LIG529O15 & LIG529H49 & GLN506OE1 & 16.184\tabularnewline
LIG529O7 & LIG529H42 & SER373O & 12.388\tabularnewline
TRP436NE1 & TRP436HE1 & LIG529O12 & 9.79\tabularnewline
SER375OG & SER375HG & LIG529O1 & 9.391\tabularnewline
ASN440ND2 & ASN440HD21 & LIG529O12 & 8.492\tabularnewline
GLN506NE2 & GLN506HE21 & LIG529O22 & 8.192\tabularnewline
LIG529O20 & LIG529H51 & ASN343O & 7.592\tabularnewline
LIG529O10 & LIG529H45 & SER375O & 7.393\tabularnewline
ASN439ND2 & ASN439HD21 & LIG529O15 & 6.893\tabularnewline
LIG529O40 & LIG529H77 & ASN440OD1 & 6.893\tabularnewline
ASN440ND2 & ASN440HD21 & LIG529O14 & 6.294\tabularnewline
LIG529O3 & LIG529H3O & ALA372O & 6.094\tabularnewline
LIG529O39 & LIG529H76 & ASP405OD1 & 5.894\tabularnewline
LIG529O27 & LIG529H74 & ASN343OD1 & 5.894\tabularnewline
ASN440ND2 & ASN440HD21 & LIG529O33 & 5.594\tabularnewline
ARG408NH1 & ARG408HH11 & LIG529O39 & 4.695\tabularnewline
TYR508OH & TYR508HH & LIG529O10 & 4.695\tabularnewline
LIG529O12 & LIG529H47 & ASN440OD1 & 4.695\tabularnewline
LIG529O27 & LIG529H74 & ASN343O & 4.196\tabularnewline
ALA344N & ALA344H & LIG529O27 & 3.896\tabularnewline
LIG529O39 & LIG529H76 & ASP405O & 3.696\tabularnewline
ARG408N & ARG408H & LIG529O39 & 3.497\tabularnewline
ASN437N & ASN437H & LIG529O6 & 3.197\tabularnewline
LIG529O21 & LIG529H68 & ASN440OD1 & 3.097\tabularnewline
ASN343ND2 & ASN343HD21 & LIG529O27 & 2.398\tabularnewline
LIG529O8 & LIG529H43 & ASN437OD1 & 2.398\tabularnewline
ASN439ND2 & ASN439HD21 & LIG529O8 & 2.298\tabularnewline
LIG529O20 & LIG529H51 & ALA344O & 1.998\tabularnewline
LIG529O21 & LIG529H68 & ASN440ND2 & 1.898\tabularnewline
LIG529O27 & LIG529H74 & PHE342O & 1.798\tabularnewline
LIG529O13 & LIG529H48 & PHE342O & 1.698\tabularnewline
ALA344N & ALA344H & LIG529O20 & 1.499\tabularnewline
SER375OG & SER375HG & LIG529O6 & 1.399\tabularnewline
ARG408NE & ARG408HE & LIG529O39 & 1.199\tabularnewline
LIG529O27 & LIG529H74 & THR345OG1 & 1.199\tabularnewline
LYS378NZ & LYS378HZ1 & LIG529O25 & 1.099\tabularnewline
\bottomrule
\end{longtable}

Table-12. Dominant Hydrogen Bond Donors and Acceptors In MD Simulation
Between Spike Protein and Pleuran of SARS-CoV-2.\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllll@{}}
\toprule
\begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Ligands\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
hERG Blockers \textsuperscript{++}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
H-HT\textsuperscript{++}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
DILI\textsuperscript{++}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
AMES \textsuperscript{++}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
ROAT \textsuperscript{++}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
FDAMDD \textsuperscript{++}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
SS \textsuperscript{++}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
CARC\textsuperscript{++}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
EC\textsuperscript{++}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
EI \textsuperscript{++}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
RT \textsuperscript{++}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
ERA \textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
GA \selectlanguage{english}\textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
+ \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
+ \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
+ \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
+ \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
+ \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
ERPO \selectlanguage{english}\textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
+ \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
+ \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
+ \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
PLEU \selectlanguage{english}\textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
+\selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
- \selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

Table-13. Systemic toxicity parameters of the ligands

\selectlanguage{english}\textsuperscript{+} Eritadenine (ERA), Ergosterol Peroxide (ERPO),
Gallic Acid (GA), Pleuran (PLEU)

\selectlanguage{english}\textsuperscript{++} AMES Test, Carcinogenicity (CARC), Drug Induced
Liver Injury (DILI), Eye corrosion (EC), Eye Irritation (EI), human
Ether-a-go-go related potassium channel blockers (hERG), Human
Hepatotoxicity (H-HT), Rat Oral Acute Toxicity (ROAT), Respiratory
Toxicity (RT) and Skin Sensitization (SS).

\textsuperscript{SS} Negative or no toxicity (-), Positive or in
probability of being actively toxic (+).\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllllll@{}}
\toprule
Ligands & NR-AR \textsuperscript{++} & NR-AR- LBD \textsuperscript{++} &
NR-AhR \textsuperscript{++} & NR- Aromatase\textsuperscript{++} & NR- ER
\textsuperscript{++} & NR-ER-LBD \textsuperscript{++} & NR-PPAR-\selectlanguage{greek}γ
\selectlanguage{english}\textsuperscript{++} & SR-ARE \textsuperscript{++} & SR-ATAD5
\textsuperscript{++} & SR-HSE \textsuperscript{++} & SR-MMP
\textsuperscript{++} & SR-p53 \textsuperscript{++}\tabularnewline
\midrule
\endhead
ERA \textsuperscript{+} & - \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§}
& -\selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} &
- \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} &
- \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} &
- \selectlanguage{ngerman}\textsuperscript{§}\tabularnewline
GA \selectlanguage{english}\textsuperscript{+} & - \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} &
+ \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} & + \selectlanguage{ngerman}\textsuperscript{§} &
- \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} &
- \selectlanguage{ngerman}\textsuperscript{§} & + \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} &
- \selectlanguage{ngerman}\textsuperscript{§}\tabularnewline
ERPO \selectlanguage{english}\textsuperscript{+} & - \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§}
& - \selectlanguage{ngerman}\textsuperscript{§} & + \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§}
& + \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} & + \selectlanguage{ngerman}\textsuperscript{§}
& - \selectlanguage{ngerman}\textsuperscript{§} & + \selectlanguage{ngerman}\textsuperscript{§} & + \selectlanguage{ngerman}\textsuperscript{§}
& + \selectlanguage{ngerman}\textsuperscript{§}\tabularnewline
PLEU \selectlanguage{english}\textsuperscript{+} & + \selectlanguage{ngerman}\textsuperscript{§} & +\selectlanguage{ngerman}\textsuperscript{§}
& - \selectlanguage{ngerman}\textsuperscript{§} & + \selectlanguage{ngerman}\textsuperscript{§} & + \selectlanguage{ngerman}\textsuperscript{§}
& + \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§}
& + \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§} & - \selectlanguage{ngerman}\textsuperscript{§}
& - \selectlanguage{ngerman}\textsuperscript{§}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

Table-14. Tox21 Pathway Parameters for the ligands

\selectlanguage{english}\textsuperscript{+} Eritadenine (ERA), Ergosterol Peroxide (ERPO),
Gallic Acid (GA), Pleuran (PLEU).

\selectlanguage{english}\textsuperscript{++} Androgen Receptor (NR-AR), Androgen Receptor Ligand
Binding Domain (NR- AR- ABD), Antioxidant Response Element (SR-ARE),
Aryl Hydrogen Receptor (NR- AhR), Aromatase enzyme (NR-Aromatase),
ATPase family AAA domain-containing protein 5 (SR-ATAD5), Estrogen
Receptor (NR-ER), Estrogen Receptor Ligand Binding Domain (NR-ER-LBD),
Heat Shock Factor Response Element (SR-HSE), Mitochondrial Membrane
Potential (SR-MMP), Peroxisome Proliferator- Activated Receptor Gamma
(NR-PPAR-\selectlanguage{greek}γ\selectlanguage{english}) and p53 binding site (SR-p53).

\selectlanguage{ngerman}\textsuperscript{§} Negative or no toxicity (-), Positive or in
probability of being actively toxic (+).\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
Ligands & ATR\textsuperscript{++} & GCR \textsuperscript{++} & NON-GCR
\textsuperscript{++} & SSR\textsuperscript{++} & AQTR \textsuperscript{++}
& NONBIOR\textsuperscript{++} &
SChEMBLR\textsuperscript{++}\tabularnewline
\midrule
\endhead
ERA \textsuperscript{+} & No Alerts & No Alerts & No Alerts & No Alerts
& No Alerts & 1 Alert & No Alerts\tabularnewline
GA\textsuperscript{+} & No Alerts & No Alerts & No Alerts & 7 Alerts &
No Alerts & 1 Alert & 1 Alert\tabularnewline
ERPO \textsuperscript{+} & No Alerts & No Alerts & No Alerts & No Alerts
& 1 Alert & No Alerts & 1 Alert\tabularnewline
PLEU\textsuperscript{+} & No Alerts & No Alerts & No Alerts & No Alerts
& 2 Alerts & 1 Alert & No Alerts\tabularnewline
\bottomrule
\end{longtable}

Table-15. Toxicophore Rules

\textsuperscript{+} Eritadenine (ERA), Ergosterol Peroxide (ERPO),
Gallic Acid (GA), Pleuran (PLEU)

\textsuperscript{++} Acute Toxicity Rule (ATR), Aquatic Toxicity Rule
(AQTR), Genotoxic Carcinogenicity Rule, Non Biodegradable Rule
(NONBIOR), Non Genotoxic Carcinogenicity Rule (NON-GCR), SureChEMBL Rule
(SChEMBLR), Skin Sensitization Rule.

\textbf{8. FIGURE LEGENDS:}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\begin{minipage}[b]{0.48\columnwidth}\raggedright\strut
Figure\_1\strut
\end{minipage} & \begin{minipage}[b]{0.48\columnwidth}\raggedright\strut
a- Main Protease (MPro) of SARS-CoV-2 with active residues in green. b-
Spike Protein of SARS-CoV-2 with active residues in green.\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Figure\_2\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
a- Docked eritadenine in the pocket of Mpro of SARS-CoV-2 where the
pocket is in greyish white and the ligand in Licorice. a1- Eritadenine
interaction with Mpro in 2D structure is given in crimson, bond
formation in green and amino acids to which they were formed in black
and other amino acidic interaction in yellow. b- Docked eritadenine in
the pocket of Spike Protein of SARS-CoV-2 where the pocket is in greyish
white and the ligand in Licorice. b1- Eritadenine interaction with Spike
Protein in 2D structure is given in crimson, bond formation in green and
amino acids to which they were formed in black and other amino acidic
interaction in yellow. c- Docked Gallic Acid in the pocket of Mpro of
SARS-CoV-2 where the pocket is in greyish white and the ligand in
Licorice. c1- Gallic Acid interaction with Mpro in 2D structure is given
in crimson, bond formation in green and amino acids to which they were
formed in black and other amino acidic interaction in yellow. d- Docked
Gallic Acid in the pocket of Spike Protein of SARS-CoV-2 where the
pocket is in greyish white and the ligand in Licorice. d1- Gallic Acid
interaction with Spike Protein in 2D structure is given in crimson, bond
formation in green and amino acids to which they were formed in black
and other amino acidic interaction in yellow. e- Docked Ergosterol
Peroxide in the pocket of Spike Protein of SARS-CoV-2 where the pocket
is in greyish white and the ligand in Licorice. e1- Ergosterol Peroxide
interaction with Mpro in 2D structure is given in crimson, bond
formation in green and amino acids to which they were formed in black
and other amino acidic interaction in yellow. f- Docked Ergosterol
Peroxide in the pocket of Spike Protein of SARS-CoV-2 where the pocket
is in greyish white and the ligand in Licorice. f1- Ergosterol Peroxide
interaction with Spike Protein of SARS-CoV-2 in 2D structure is given in
crimson, bond formation in green and amino acids to which they were
formed in black and other amino acidic interaction in yellow. g- Docked
Pleuran in the pocket of Mpro of SARS-CoV-2 where the pocket is in
greyish white and the ligand in Licorice. g1- Pleuran interaction with
Mpro in 2D structure is given in crimson, bond formation in green and
amino acids to which they were formed in black and other amino acidic
interaction in yellow. h- Docked Pleuran in the pocket of Spike Protein
of SARS-CoV-2 where the pocket is in greyish white and the ligand in
Licorice h1- Pleuran interaction with Spike Protein of SARS-CoV-2 in 2D
structure is given in crimson, bond formation in green and amino acids
to which they were formed in black and other amino acidic interaction in
yellow.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Figure\_3\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
a- Root Mean Square Deviation (RMSD) of Ligands bound to Main Protease
of SARS-CoV-2 (PDB ID: 6LU7). b- Root Mean Square Fluctuation (RMSF) of
Ligands bound to Main Protease of SARS-CoV-2 (PDB ID: 6LU7).\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Figure\_4\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
a- Root Mean Square Deviation (RMSD) of Ligands bound to Spike Protein
of SARS-CoV-2 (PDB ID: 6YOR). b- Root Mean Square Fluctuation (RMSF) of
Ligands bound to Spike Protein of SARS-CoV-2 (PDB ID: 6YOR).\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Figure\_5\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Top 15 Targets for Eritadenine\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Figure\_6\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
All Targets for Gallic Acid\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Figure\_7\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Top 15 Targets for Ergosterol Peroxide\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Figure\_8\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
All Targets for Pleuran\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{9. SUPPORTING INFORMATION:}

The supporting information containing the \emph{in silico} target
prediction from Swiss Target Prediction is given as supporting
information along with this article.

The supporting information file has output files from
SwissTargetPrediction website for entered ligands of interest such as
eritadenine, gallic acid, ergosterol peroxide and pleuran. Each of the
output file has possible targets for the same ligand, the target's
common name, Uniprot ID of the targets, ChEMBL ID of individual targets,
Target Class and Probability in a tabular format.

\textbf{10. DATA AVAILABILITY STATEMENT:}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

\textbf{11. CONFLICTS OF INTEREST:}

The authors declare that there is no conflict of interest.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4/Figure-4}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-5/Figure-5}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-6/Figure-6}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-7/Figure-7}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-8/Figure-8}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

