Asian Journal of Research in Pharmaceutical Sciences.

11(1): January - March, 2021

ISSN 2231–5640 (Print) Available online at

2231–5659 (Online) www.anvpublication.org
DOI:

Vol. 11 |Issue-01| Asian Journal of

January - March | 2021 Research in Pharmaceutical Sciences
Home page www. ajpsonline.com

RESEARCH ARTICLE

Virtual Screening of Pentahydroxyflavone – A Potent COVID-19 Major

Protease Inhibitor
S. Bhavanisha Rithiga, S. Shanmugasundaram*
Department of Biotechnology, Sri Shakthi Institute of Engineering and Technology, Chinniyampalayam,
Coimbatore-641062, Tamil Nadu, India.
*Corresponding Author E-mail: drsundaram@gmail.com

ABSTRACT:
COVID-19, is a newly spread pandemic disease and is primarily transmitted through nasal droplets which then
causes mild to severe respiratory illness. Now this has been the major challenge to the world to tackle and save
the lives of people without a proper vaccine. Therefore, there is an urgent need to screen for antiviral bioactive
compounds to inhibit COVID-19 development. Among others, the major viral protease is an important target as
this enzyme plays animportant role in the development of the virus. We were particularly looking for compounds
from fruits that are capable of binding to the COVID-19 major protease. Morin, a pentahydroxyflavone is
commonly present in guava, tea, kiwi and strawberry. It has been shown to have antiviral, antibacterial and
antioxidant properties. Hence, the compound Morinwas virtually screened for its ability to bind to major 3CL
protease (Mpro) of COVID-19. The active site of the enzyme has dyad amino acids; HIS41 and CYS 145. This
compound binds to HIS41 in the active site of the protease.The binding ability was studied using AutodockVina.
The binding ability was compared to a synthetic ligand N3 which is already complexed with the main protease
with the PDB Id: 7BQY. While the binding efficiency of N3 is -4.6kcal/mole, it is -7.6kcal/mole for Morin. Also
the LIPINSKI analysis has shown its drug like character. The ADMET analysis has shown that it has no
genotoxicity and low drug induced toxicity. Owing to its presence in fruits like strawberry, it could well be a
prophylactic medication.

KEYWORDS: Morin, Bioactive plant compounds, Flavonoids, COVID-19, Respiratory illness, Mpro, 7BQY,
Catalytic site of COVID-19.

INTRODUCTION: The recently found CoV is named as SARS-CoV 2 as it

Coronaviruses (CoVs) cause severe respiratory and
gastrointestinal infections which is transmitted through
the hosts like human, mammals, fish and avian. The
emergence of Severe Acute Respiratory Syndrome
coronavirus (SARS-CoV) outbreaks in 2002-2003 was
followed by Middle East Respiratory Syndrome (MERS-
CoV).
Received on 11.11.2019 Modified on 19.12.2019
Accepted on 21.01.2020 ©Asian Pharma Press All Right Reserved
Asian J. Res. Pharm. Sci. 2021; 11(1):
DOI:
1
shows some resemblance towards the SARS-CoV1,2,3,4.
Average incubation period of COVID-19 ranges from 0
to 24 days. The basic reproductive number of COVID-19
at the early phase of different prediction models is higher
than that of SARS and MERS. The release of large
amount of viruses at the early phase of infection has
posed enormous challenges for containing the spread of
COVID-195.
Currently, there are no specific treatments and therapies
for curing COVID-19 and research and investigations
regarding the outbreak of COVID-19 are going on. But
 Asian Journal of Research in Pharmaceutical Sciences. 11(1): January - March, 2021

some preventive and control measures are being taken that morin has blood thinning property i.e. anti-platelet
for the supportive management of complications6,7. activity13.
Some preliminary studies have investigated that the
Lopinavir/Ritonavir can be used to treat coronavirus. Experimental Section:
And also other drugs like Nucleoside analogues, Protein/Macromolecule:
Neuraminidase inhibitors, Remdesivir8, peptide EK1, COVID-19 3CLpro/Mpro (PDB ID:7BQY) structure
abidol, RNA synthesis inhibitors such as TDF, 3TC, was obtained from PDB (https://www.rcsb.org/and -
anti-inflammatory drugs such as hormones could be the https://www.wwpdb.org/pdb?id=pdb_00007bqy) in .pdb
treatment options for 2019-nCoV. Still the efficacy and format. PDB is an archive for the crystal structures of
the safety are needed to be confirmed by clinical biological macromolecules, worldwide14. PBD ID:
studies9. 7BQY is the crystal structure of COVID-19 main16
protease in complex with an inhibitor N3.It contains two
Liu et al. (2020) have successfully crystallized the main chains A and B. Chain A was used for macromolecule
protease (Mpro)/chymotrypsin-like protease (3CLpro) preparation as it plays a major role in the metabolic
from COVID-19, which has been structured and process in the virus. The native ligand for 7BQY isn-[(5-
repositioned in the Protein Data Bank (PDB) and is methylisoxazol-3-yl) carbonyl] alanyl-l-valyl-n~1~-
accessible by the public. This protease is represented as ((1r,2z)-4-(benzyloxy)-4-oxo-1-{[(3r)-2-oxopyrrolidin-
the potential target for the inhibition of CoV 3-yl]methyl}but-2-enyl)-l-leucinamide. The resolution of
replication.It processes the polyproteins that are the protease is 1.70 angstrom. The experimental analysis
translated from the viral RNA. Coronavirus protease is a of this protease was done by X-ray diffraction method.
cysteine protease. The rationale of this study is due to This viral protein is found in severe acute respiratory
the functional importance of Mpro in the viral life cycle, syndrome coronavirus 2 and is synthetically altered by
together with the absence of closely related homologues complexing the protein with an inhibitor N315.
in humans and therefore Mpro has been identified as an
attractive target for antiviral drug design. The main Ligand:
protease (PDB ID: 7BQY) is the crystal structure of The 3-dimensional (3D) structure is obtained from
COVID-19 main protease (mpro) in complex with an PubChem (http://pubchem.ncbi.nlm.nih.gov/), in .sdf
inhibitor N3, which has been taken as the protein target format. PubChemis a chemical substance and bioassay
in this study. activities repository databases. The compound used in
the present study is morin (CID_5281670)16.
Scientists all over the world are desperately looking for
effective compounds that can be used against this virus. Drug-likeness of the ligand:
Natural compounds with high bioavailability and low The ligand has to be scanned for its drug likeness. This
cytotoxicity seem to be the most effective in this regard. factor is determined by Lipinski’s rule of five. This
Naturally occurring compounds especially ligand is scanned in online software by Supercomputing
phytochemicals are used for ages to cure diseases and facility for Bioinformatics and Computational biology,
infections. Flavonoids are secondary metabolites IIT, Delhi http://www.scfbioiitd.res.in/software/
produced by plants and play very important roles in plant drugdesign/lipinski.jsp. It has two steps for getting the
physiology, possessing a variety of potential biological results. In step 1 the .sdf file of morin from Pubchem
benefits such as antioxidant, anti-inflammatory, which is saved is chosen. Then in step 2, the pH is set as
anticancer, antibacterial, antifungal and antiviral 7. After two steps it is submitted then the result will be
activities. Different flavonoids including both flavones displayed. This will give the molecular mass, high
and flavonols have been quite thoroughly investigated lipophilicity, hydrogen donor, hydrogen acceptor and
for their potential antiviral properties and many of them molar refractivity.
showed significant antiviral response in both in vitro as
well as in vivo studies10. In the present study, we In silico toxicity prediction:
investigated morin as potential inhibitor candidate for In silico toxicity assessment is one of the methods where
COVID-19 Mpro. Morin (2’, 3, 4’5, 7- the compound is analysed and predicted via
Pentahydroxyflavone) also called morin hydrate is a computational methods. Determination of toxicity of the
natural flavonoid found most commonly in almonds, ligand is important in drug designing. The toxicity
guava, onion, kiwi and strawberry has antibacterial, and prediction is necessary to identify the harmful effect of
anticancer properties. Some studies have shown that it the ligand on human. This assessment has been done
also has antiviral property11. through an online toxicity predicting tool. AdmetSAR
(http://lmmd.ecust.edu.cn/admetsar1/predict/is a
The existing US Food and Drug Administration (FDA) comprehensive source and a free tool for evaluating the
have approved that anticoagulant called heparin to lower ADMET (Absorption, Distribution, Metabolism,
the SARS-CoV-2 infection12. Some studies have proved Excretion and Toxicity) properties of a compound.
2
 Asian Journal of Research in Pharmaceutical Sciences. 11(1): January - March, 2021

Active Sites: RESULTS:

The 7BQY protein has a synthetic inhibitor N3. The
active sites were determined by the substrate binding
pocket of the inhibitor N317. The determination of amino
acid in the active site was predicted18 and the Grid box
was placed on this region for the evaluation of docking
results. The active sites of the target and ligand binding
sites are listed below:
Active site of the target (based on N3 Ligand binding sites
position) (predicted)
H41, Y54, L141, N142, G143, C145, Catalytic dyad i.e. H41
E166, P168, Q189, T190, A191 and C145
Preparation and optimisation of target and ligand:
The protein is saved in .pdb format from PDB database.
Then the protein is optimised using Autodock tool. The
optimisation algorithms are the main algorithm used to
find the best binding pose of the ligand in protein-ligand
docking.The Autodock version 4.2 which is supported
by Autodock tools and MGL tools used for protein
preparation by removing water and the inhibitor N3, and
then adding a polar hydrogen group as well as Kollmann
charges. Then the protein converted into .pdbqt format
which has been prepared for docking. The ligand was
obtained in .sdf format from Pubchem. It has been Table
native ligand structure
prepared to a PDB format using a PyMol visualizer,
open source software for molecular visualisation. Ligand
optimisation was performed by PyMol19, and saved in
.pdb format. Then the ligand was converted into .pdbqt
formatusing AutoDock tools for the next process of
docking.
The COVID-19 main protease and the ligand 3D
structures are shown in Table1. The interacting residues,
hydrogen bonds interacting residues and polar non-polar
interactions of the ligands morin and N3 which are
determined using PyMol tool are shown in Table2. The
RMSD (the root-mean-square deviation of atomic
positions) were obtained for 9 poses and presented in
Table3. Histogram showing the docking results between
7BQY and the compounds such as morin and N3 has
been shown in Fig 1. the interaction of ligand morin with
the target, 7BQY and the distance between the
interaction and the amino acids surrounding the
ligandare shown in Fig. 2. the interaction of ligand N3
with the target, 7BQY and the distance between the
interaction and the amino acids surrounding the
ligandare shown in Fig.3. Compared to the synthetic
ligand N3, the natural ligand morin has shown less free
energy requirement to bind to the target and lower
RMSD values indicate its biding distances are much
closer to the protein than N3. The comparison of docking
results of morin and N3 and their interacting amino acids
are shown in Table 4.
1: Protein target structure (PyMol version 1.7.4.5) and
COVID-19 Main N3 MORIN
Protease (PDB ID
7BQY)

Molecular docking:
Autogrid was used to determine the native ligand
position on the binding site by arranging the grid
coordinates (X, Y, Z). By regulating the genetic
algorithm (GA) parameters, using 10 runs of the GA
criteria, the ligand tethering of the protein was
performed. The docking analyses were performed by
Autodock 4.2 and PyMol version 1.7.4.5. By running the
Autodock the binding affinities and the rmsd values can
be calculated.

Table 2: The interacting residues, hydrogen bonds interacting residues and polar non-polar interactions of the ligands morin and N3
which are determined using PyMol tool
Ligand Interacting residues Number of Hydrogen Hydrogen bond Other interaction Number of polar and non
bond interacting residues residues polar interaction
Morin T26 Pose 1: 1 H41 T26 Non polar interaction:
H41 Pose 2: 2 N142 Pose 1: 1
N142 Pose 3: 2 S144 Pose 2: 2
S144 Pose 4: 5 H163 Pose 3: 2
H163 Pose 5 : 1 E166 Pose 4: 4
E166 Pose 6: 1 Q189 Pose 5: 1
Q189 Pose 7: 2 T190 Pose 6: 1
T190 Pose 8: 3 Pose 7 :1
Pose 9: 2 Pose 8: 3
Pose 9: 2
Polar interaction:

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 Asian Journal of Research in Pharmaceutical Sciences. 11(1): January - March, 2021

Pose 4: 1
Pose 7: 1
N3 T26 Pose 1: 1 H41 T26 Non-polar interaction
H41 Pose 2: 3 Y54 Pose 1: 1
Y54 Pose 3: 5 R138 Pose 2: 3
R138 Pose 4: 5 L141 Pose 3: 5
L141 Pose 5: 1 N142 Pose 4: 4
N142 Pose 6: 1 G143 Pose 5: 1
G143 Pose 7: 2 S144 Pose 6: 1
S144 Pose 8: 3 H163 Pose 7: 1
H163 Pose 9: 2 E166 Pose 8: 3
E166 Q189 Pose 9: 2
Q189 T190 Polar interaction
T190 T199 Pose 4: 1
T199 Pose 7: 1

Table 3: Comparison of the analysed results of morin and inhibitor

N3
Poses Binding Affinity Binding Affinity RMSD of RMSD
of Morin of N3 (kcal/mol) Morin of N3
(kcal/mol)
1 -7.6 -4.6 0 0
2 -7.5 -4.4 1.744 3.415
3 -7.2 -4.4 2.094 29.494
4 -7.1 -4.4 4.243 6.260
5 -7.0 -4.3 3.294 3.545
6 -6.9 -4.3 3.102 6.260
7 -6.7 -4.3 4.052 4.856
8 -6.6 -4.3 5.153 3.636
9 -6.5 -4.3 4.607 9.322
Fig. 1: Histogram showing the docking results between 7BQY and
the compounds such as morin and N3 (The binding affinity is
shown in minus kcal/mol)

Pose 1 Pose 2 Pose 3

Pose 4 Pose 5 Pose 6

Pose 7 Pose 8 Pose 9

Fig. 2: The interaction of ligand morin with the target, 7BQY and the distance between the interaction and the amino acids surrounding
the ligand.

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 Asian Journal of Research in Pharmaceutical Sciences. 11(1): January - March, 2021

Pose 1 Pose 2 Pose 3

Pose 4 Pose 5 Pose 6

Pose 7 Pose 8 Pose 9

Fig. 3: The interaction of ligand N3 with the target, 7BQY and the distance between the interaction and the amino acids surrounding the
ligand

Table 4: shows the comparison of docking results of morin and N3.

Properties N3
The active site residues that are bound by the ligand H41, Y54, N142, H163, E166
Number of hydrogen bonds formed Pose 1: 3(2 interacts),
Pose 2: 1(1 interacts),
Pose 4: 4(3 interacts),
Pose 5: 1(1 interacts),
Pose 6: 2(2 interacts),
Pose 8: 1(1 interacts).
Free energy of binding Pose 1: 5.06 kcal/mol
Pose 2: 4.74 kcal/mol
Pose 4: 3.94 kcal/mol
Pose 5: 3.76 kcal/mol
Pose 6: 3.72 kcal/mol
Pose 8: 3.12 kcal/mol
Morin
T26, H41, N142, S144, H163, E166, Q189, T190
Pose 2: 3(2 interacts),
Pose 3: 5(2 interacts),
Pose 4: 6(4 interacts),
Pose 6: 1(1 interacts),
Pose 7: 2(1 interacts).
Pose 2: 5.13 kcal/mol
Pose 3: 5.12 kcal/mol
Pose 4: 4.39 kcal/mol
Pose 6: 4.80 kcal/mol
Pose 7: 4.69 kcal/mol

Lipinski’s rule of five states that a compound can be ADMET Profile:

orally active if its molecular mass is less than 500
Dalton, the hydrogen donor should not be more than 5,
the hydrogen acceptor should not be more than 10, the
octanol water partition coefficient (Log P) should not
exceed 5 and the molar refractivity should be between 40
and 13019.The drug likeness score of the ligand morin is
given below:
ADMET stands for Absorption, Distribution,
Metabolism, Excretion and Toxicity. The prediction of
the ADMET properties plays an important role in the
drug design process because these properties account for
the failure of about 60% of all drugs in the clinical
phases21. the ADMET analysis has shown that it is not
genotoxic and the drug induced toxicity is low.

Molecular mass: 302.00 DISCUSSION:

hydrogen bond donor: 5 Several compounds, such as flavonoids from plants and
hydrogen bond acceptors: 7 food, have been reported to show antiviral bioactivities22.
LogP: 2.010900 The present study has investigated morin as a potent
inhibitor of the COVID-19 Mpro. An in silico analysis
Molar Refractivity: 74.050476

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 Asian Journal of Research in Pharmaceutical Sciences. 11(1): January - March, 2021

showed that morin has better affinity towards the active also it allows sidechains in the macromolecule to be
site residues of the protein. flexible. As before, rigid docking is blindingly fast, and
high-quality flexible docking can be done in around a
The results of docking analysis (see table 4) showed that minute. Up to 40,000 rigid dockings can be done in a
morin forms H-bonds with the 7BQY amino acids H41, day on one CPU. AutoDock 4.0 now has a free-energy
N142, S144, H163, E166 and Q189 which are the scoring function that is based on a linear regression
substrate binding residues of the inhibitor N3 present in analysis, the AMBER force field, and an even larger set
the crystal structure of 7BQY. All the H-bonds interact of diverse protein-ligand complexes with known
with the COVID-19 Mpro active sites. The binding inhibition constants thanwhat is used in AutoDock 3.025.
energy results are related to the number of H-bonds
formed with the active site pocket of COVID-19 Mpro. CONCLUSION:
For morin the binding affinities are -7.6,-7.5, -7.2, -7.1, - Currently, COVID-19 has emerged as a threat to the
7, -6.9, -6.7, -6.6, -6.5 kcal/mol. It has been determined global health. The present virtual study has shown that
using the Autodock Vina tool for efficient result.And for the naturally occurring plant compounds could inhibit
the synthetic ligand N3 the binding affinities are -4.6, - the COVID-19 infection pathway by inhibiting the 3CL
4.4, -4.4 -4.4, -4.3, -4.3, -4.3, -4.3 and -4.3 kcal/mol. protease. Morinrequires the lowest binding energy to
When the affinities are compared the energy required for bind to 3CL protease. The presence of morin in
binding affinity of morin was lower than that of N3 strawberry has been analysed in earlier studies26. Due to
which shows that morin is more efficient in binding than its antiviral property it could be an effective drug against
the N3. COVID-19. Also the toxicity has also been checked
which shows that morin is non-toxic and can be used for
The rationale of this study is due to the functional drug designing by the results of Lipinski’s rule.Also the
importance and its properties. The main protease has ADMET analysis has shown that it is not genotoxic and
been selected due to its function in the viral life cycle the drug induced toxicity is low.
and the ligand morin is selected due toits blood thinning
property and also its presence in edible fruits. ACKNOWLEDGEMENT:
We would like to thank the faculty in the Department of
Morin is a bioactive flavonoid which has been shown to Biotechnology, the Principal and the Management of
have an anti-inflammatory property. Also it has been SIET College for permitting us to use the facility.
reported that morin hydrate inhibits platelet activation
through inhibition of the PLCγ2–PKC cascade and CONFLICT OF INTEREST:
subsequent inhibition of Akt and MAPK activation, The authors declare no conflict of interest
thereby inhibiting platelet aggregation23.
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UGT catelyzed - 0.5000
Carcinogenicity (binary) - 1.0000

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 Asian Journal of Research in Pharmaceutical Sciences. 11(1): January - March, 2021
Carcinogenicity (trinary)
Eye corrosion
Eye irritation
Ames mutagenesis
Human either-a-go-go inhibition
micronuclear
Hepatotoxicity
Acute Oral Toxicity (c)
Estrogen receptor binding
Androgen receptor binding
Thyroid receptor binding
Glucocorticoid receptor binding
Aromatase binding
PPAR gamma
Honey bee toxicity
Biodegradation
crustacea aquatic toxicity
Fish aquatic toxicity
Non-required 0.6985
- 0.9890
+ 0.9661
+ 0.6400
- 0.8932
+ 0.9400
+ 0.7500
II 0.6238
+ 0.8581
+ 0.8744
+ 0.6361
+ 0.9139
+ 0.8241
+ 0.8913
- 0.4916
- 0.7750
- 0.5700
+ 0.8979