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2668| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
Research Article
In-Silico
Study of the Inhibitory Effect of Some
Flavonoids Compounds and their Derivatives on SARS-
COV-2
RAFEEF AMER ABDUL-JABAR1*, SABAA ALI MOHAMMED AL-FADAL2
1Department of Clinical Laboratory Sciences, College of Pharmacy, University of Basra, Iraq
2Department of Pharmacognosy and medicinal plants, College of Pharmacy, University of Basra, Iraq
Email ID: sabaal.fadal@gmail.com
Received: 20.04.20, Revised: 10.05.20, Accepted: 05.06.20
ABSTRACT
The pandemic of Coronavirus Disease 2019 forms a big threat to all people in the world around us. In Iraq, there
is a direct increase in the incidence, with a slight decrease in the mortality rate, and that leads us to attempt to
find any way to stop or lessen the virus's harmful symptoms. In the current study, we used molecular docking to
detect the probable inhibitory effect of fifteen natural compounds of some Flavonoids and their derivatives and
two antiviral drugs against two of very important SARS-COV-2 proteins the papain like protease (PLpro) and
RNA dependent RNA polymerase (RdRp) that was performed using Molecular Operating Environment
software(MOE).
All the chosen flavonoids and their derivatives, plus the two antiviral drugs docked in the active sites of the viral
proteins (PLpro), some of the natural flavonoids like Glycitein 7-O-glucuronide and Theaflavin, gives energy
complex scores about -6.96308947 and -6.99058199 Kcal/mol which is better than the energy score is given by
Sofosbuvir and Darunavir -6.81020832 and -6.93942785 Kcal/mol respectively. And the docking of the compounds
into the active sites of (RdRp) protein gives energy binding scores for Theaflavin monogallate -7.84163618
kcal/mol and that better than the complex's score given by docking of the Sofosbuvir and Darunavir into the same
protein which gives -7.30999422 and -7.67598867 kcal/mol respectively. That’s mean these flavonoids and their
derivatives can be used as COVID-19 treatment. Otherwise, the infected people with COVID-19 can consume
food rich with these Flavonoids to inhibit the virus or at least decrease its symptoms.
Also from docking of flavonoids into both viral proteins, we can notice that all-natural compounds reported
energy binding scores, and the Flavonoid derivatives have a better energy binding score than flavonoid themselves.
Keywords: Flavonoids, Papain like protease, RdRp, Flavonoid derivatives, Theaflavin, 6WX4, 7BV2.
INTRODUCTION
Since December 2019 all the world around us
suffering from a pandemic of Coronavirus Disease
2019 (COVID-19). It is the most recently
discovered coronavirus that causes infectious
zoonotic disease (which can infect a broad range of
hosts including humans) named severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2)
[1,2]. The virus belongs to the family
Coronaviridae, which has four subgroups the alpha
(α), beta (β), gamma (γ), and delta (δ) coronavirus
and the ‘common human coronaviruses’ are 229E
(α coronavirus), NL63 (α coronavirus), OC43 (β
coronavirus) and HKU1 (β coronavirus) [3]. They
usually cause a respiratory infection extending
between the common cold and severe state
diseases, virtually over the past two decades,
coronaviruses (CoVs) have been associated with
significant disease outbreaks in East Asia and the
Middle East, severe acute respiratory syndrome
(SARS) and the Middle East respiratory syndromes
(MERS) began to emerge in 2002 and 2012,
respectively [2]. At present-day, the novel
coronavirus (SARS-CoV-2), causes a disease
characterized by a respiratory syndrome with a
variable degree of severity, ranging from a mild
upper respiratory tract illness to severe interstitial
pneumonia and acute respiratory distress syndrome
[4].
COVID-19 is typically rapidly spread from one
person to another via respiratory droplets produced
during coughing and sneezing [3] and generally
has a less severe clinical picture than MERS and
SARS but it can spread in the community more
easily and that made this virus a global health
threat with its continuing pandemic in many
countries and regions [2,4]. Today in Iraq the
number of infected people reaches 168,290 with a
mortality rate of about 3.9 % with a threat of the
second wave in the next autumn and that is
relatively high percent lead us to try to find any way
to stop or lessen the harmful symptoms as well as
the very rapid spread of this virus along with the
community [5, 6].
The using of plants extracts regard as one of the
most ancient and powerful means enabled human
to survive and treat multiple of disease across
years, Despite several advancements in the field of
DOI: https://doi.org/10.31838/ijpr/2020.12.02.360
ISSN 0975-2366
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2669| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
synthetic drug chemistry and antibiotics, Today, the
world is gradually turning to plant formulations
which are known to be effective against a large list
of diseases and illnesses [7]. The plant's secondary
metabolites are a group of plant products which
have low molecular weight compounds formed
generally by specific plant`s organs, tissues, and
cells[8]. They have high pharmaceutical properties
effective for human health and widely used in the
drug and pharmaceutical industry and are include
many related metabolites like alkaloids, amines,
steroids, insecticides, and flavonoids [7].
Flavonoids are a group of polyphenolic
compounds that hold an aromatic ring bearing at
least one hydroxyl group [9]. They are commonly
found in fruits, vegetables, nuts, seeds, and honey,
etc. They are known to have medicinal properties
and play a major role in successful medical
treatments from ancient times [7]. flavonoids have
been reported on their effective antioxidants,
anticancer, antibacterial, cardioprotective agents,
anti-inflammation, immune system promoting, and
interesting candidate for pharmaceutical and
medical applications [9]. All these valuable
properties directed us to make a study by molecular
docking using Molecular Operating Environment
(MOE software) about the inhibitory effect of some
available and medically important flavonoids on
two of the more important SARS-CO-V2 proteins
the papain like protease enzyme (PLpro) [10], and
RNA dependent RNA Polymerase (RdRp) which also
known as NSP12, catalyzes the synthesis of viral
RNA [11].
MATERIAL AND METHODS
Medicinal compounds choice
In this study, we tried to select a Multiple of
medicinally reported important and more available
flavonoids and a few of their derivatives to detect
their inhibitory effect on COVID 19 (RdRp plus
PLpro) proteins. The selected flavonoids and their
derivatives are Kaempferol, Myricetin, Epicatechin,
Chrysin, Taxifolin, Glycitein, Malvidin, Theaflavins,
Pinocembrin, Naringenin, Theaflavin monogallate,
Glycitein7-O-glucuronide, Myricetin3-O-
rhamnoside, Epicatechin-o-gallate, and
Pinocembrin7-O-rhamnoside.
Preparation of both enzymes and ligands
The download of COVID-19 PLpro and RdRppr
three dimensional structures was done from Protein
Data Bank under PDB ID 6WX4 and 7BV2
respectively [12,13]. Crystallographic properties of
6WX4 and 7BV2 proteins are reported in table 1.
The more suitable region of the receptor that
forming interactions with ligands can be recognized
by the protocol of active site prediction and
isolation [14]. Then Hamiltonian PM3 (Parametric
model 3) set in MOE was used and field strengths
within the MMFF94x (Merck molecular force field)
energy of the protein was minimized. Besides, the
protein surface must be clear from water molecules
because the latter may hide the interaction region
during docking. The active sites of 6WX4 and 7BV2
were identified by using the model of site-finder set
in MOE as shown in Figure 1 and 2.
Table 1: Crystallographic properties of covid-19 proteins.
Protein
Pdb
code
Classification
Organism
Expression
system
Resolution
METHOD
Total
structure
weight
(da)
Chain
Papain like
protease
6WX4
Hydrolase
SARS-
CoV-2
Escherichia
coli
BL21(DE3)
1.66 Å
X-Ray
Diffraction
37130
D
RNA
dependent
RNA
Polymerase
7BV2
Viral Protein
SARS-
CoV-2
Spodoptera
Frugiperda
2.50 Å
Electron
Microscopy
109070
A
And Table 2 reports the major chemical structure of
the chosen flavonoids which collected from
(Chequer et al. 2013) [15]. The 2-dimensional (2D)
structures of flavonoids chemical compounds were
downloaded in SDF format from PubChem [16].
Lipinski’s physicochemical parameters rule [17, 18]
were also studied for each flavonoid (ligand) and
reported in table 3. Chemical structures of main
drugs under clinical tests for the treatment of
COVID-19 are reported in table 4 [19, 11]. Also,
both natural ligands (Flavonoids compounds) and
proposed drugs were submitted to energy
minimizing under default conditions of pH = 7 and
temperature = 300°K.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2670| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
Table 2: The chemical structures of flavonoids
Taxifolin
Chrysin
Theaflavin
Pinocembrin
Malvidin
Naringenin
Kaempferol
Myricetin
Epicatechin
Glycitein
Pinocembrin7-O-
rhamnoside
Theaflavin
monogallate
Glycitein7-O-
glucuronide
Epicatechin-3-O-
gallate
Myricetin 3-O-
rhamnoside
Table 3: Physicochemical Lipinskis parameters for flavonoids compounds.
Ligands
MW
(gm/mol)
toxicity
H-
don
H-
acc
TPSA
(A⁰)
Rot
B
Log p
Log s
Lip_Drug
l.
1.Kaempferol
287.246
Non
3
5
86
1
1.48
-2.93
1.0
2.Myricetin
319.244
Non
6
7
130.61
0
2.34
-2.20
1.0
3.Naringenin
273.264
Non
2
5
66.76
1
1.56
-2.25
1.0
4.Chrysin
256.256
Non
3
3
69.92
0
2.56
-3.06
1.0
5.Epicatechin
288.255
Non
4
5
90.15
1
2.52
-1.89
1.0
6.Glyciten
284.266
Non
0
3
27.69
1
1.73
-3.95
1.0
7.Malvidin
332.307
Non
3
6
79.15
2
1.43
-2.78
1.0
8.Pinocembrin
258.272
Non
2
4
66.76
1
1.52
-2.71
1.0
9.Taxifolin
304.253
Non
5
7
127.45
1
1.44
-2.00
1.0
10.Theaflavin
562.482
Non
6
9
139.84
0
3.61
-4.66
0.0
11.Theaflavin
monogallate
708.54
Non
11
12
254.9
3
5.26
-7.38
0.0
12.Glycitein 7-O-
glucuronide
460.391
Non
6
10
172.21
5
-0.13
-3.558
1.0
13.Myricetin 3-O-
rhamnoside
464.379
Non
8
11
206.6
3
0.53
-2.716
1.0
14.Epicatechin-o-gallate
441.368
Non
6
8
179.97
4
3.49
-3.289
1.0
15.Pinocembrin7-O-
rhamnoside
402.399
Non
4
8
116.45
3
-0.54
-2.439
1.0
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2671| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
Table 4: The chemical structure of the examined antiCOVID-19 drugs.
drugs
Chemical structure
Drug bank
Accession
Number
Lipinski’s rules
properties
value
Sofosbuvir
DB08934
MW(g/mol)
H-donor
H-acceptor
Log P(o/w)
Log S
TPSA (A⁰)
RotB
541.554
5
11
0.558
-1.275
144.57
11
Darunavir
DB01264
(EXPT00002)
MW(g/mol)
H-donor
H-acceptor
Log P(o/w)
Log S
TPSA (A⁰)
RotB
560.776978
1
7
1.595
-3.183
121.709
4
Fig.1: The active site of RNA dependent RNA polymerase (PDB 7BV2) in complex with Remdesivir.
Fig.2: The active site of Papain like protease (PDB 6WX4) enzyme inhibited by peptide inhibitor
VIR251.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2672| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
Docking and Building Complexes
Docking using the Dock module in MOE software
consists of positioning ligands into the active site of
6WX4 and 7BV2 with most of the default tools to
expect how molecules interact with the binding site
of the receptor [20]. The first docked molecules
series were proposed drugs and respective
reference inhibitors (PRD_002390 of 6WX4 and
F86 for 7BV2) to compare obtained scores with
scores from chosen ligands of flavonoids and a few
of their derivatives.
RESULTS
All the gained scores of docking of drugs and
inhibitor ligands (PRD_002390 and F86). Under
clinical test with the SARS COV2 proteins (PDB ID
6WX4 and 7BV2) were shown in table 5. As well as
the docking scores of flavonoids compounds with
the same viral proteins were shown in table 6 and
Table 7(a-o) and Table 8(a-o). the natural
flavonoids like Glycitein 7-O-glucuronide and
Theaflavin, gives energy complex scores about -
6.96308947 and -6.99058199 Kcal/mol when
docked within the SARS COV2 PLpro, while the
docking of the Theaflavin monogallate into the
active sites of RdRp viral protein gives energy
binding scores -7.84163618 kcal/mol as shown in
Figure 3 and 4.
Table 5: Score of binding for docking of SARS COV2 proteins with some drugs and inhibitor.
Drugs and Inhibitors
The score of binding (Kcal/mol)
6WX4
7BV2
1. PRD_002390
-8.20934486
/
2. F86 (Remdesivir)
/
-6.22851563
3. Sofosbuvir
-6.81020832
-7.30999422
4. Darunavir
-6.93942785
-7.67598867
Table 6: Binding score for docking of SARS COV2 proteins with choosing flavonoids and a few of their
derivatives.
Flavonoids and derivatives
The score of binding (Kcal/mol)
6WX4
7BV2
1.Kaempferol
-5.29018021
-6.12179089
2.Myricetin
-5.86744404
-5.85045195
3.Naringenin
-5.87787628
-5.97152519
4.Chrysin
-4.68946028
-5.42630672
5.Epicatechin
-5.05769491
-4.75056934
6.Glyciten
-5.25532818
-4.14114809
7.Malvidin
-5.46971416
-5.60388279
8.Pinocembrin
-5.2122879
-5.77658463
9.Taxifolin
-5.13097095
-5.547822
10.Theaflavin
-6.99058199
-6.61838436
11.Theaflavin monogallate
-6.26978922
-7.84163618
12.Glycitein 7-O-glucuronide
-6.96308947
-6.61669445
13.Myricetin 3-O-Rhamnoside
-6.19278622
-7.35158348
14.Epicatechin-O-gallate
-6.24127769
-6.42785978
15.Pinocembrin7-O-Rhamnoside
-5.98144579
-6.40977716
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2673| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
Fig.3: The2D and 3D possible interaction of Theaflavin and Glycitein-o-7glucorenoid with SARS COV2
PLpro respectively.
Fig.4: The 2D and 3D possible interaction of Theaflavin monogallate with SARS COV2 RdRp protein.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2674| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
Table 7: The theoretical binding complex gained by docking of flavonoids and their derivatives with
SARS COV2 Papain like protein ID 6WX4.
Selected
compounds
2D possible interaction of compounds
Types of binds
a. Kaempferol
The amino acid ASP 164 (H-
donor) with 2.66 A⁰ distance
and energy of -14.9
kcal/mol.
The amino acid GLN 269
form (π-H) bond with 4.31 A⁰
distance and -0.7 kcal/mol.
b. Myricetin
The (H-donor) hydrogen
bonds formed by amino
acids GLY136, ASP164, and
GLY136 with 3.04 A⁰, 2.62
A⁰and 2.86 A⁰ distances and
energy of -2.1,-28.0, and -
1.6 kcal/mol respectively.
The amino acid ASP164
(ionic) with 2.62 A⁰ distance
and -28.0 kcal/mol. And The
TYR 264 (π-H) with 4.55 A⁰
distance and energy of -1.0
kcal/mol.
c. Naringenin
The amino acid ASP164
form (H-donor) with 2.6 A⁰
and energy of –20.2
kcal/mol.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2675| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
d. Chrysin
The GLY163 form (H-donor)
bond with 2.94 A⁰ distance
and -1.5 kcal/mol. And The
amino acid TYR 264 form (π-
H) bond with 4.5 A⁰ distance
and energy of -0.6 kcal/mol.
e. Epicatechin
The amino acid ASP164
forming (H-donor) bond with
2.59 A⁰ distance and energy
of -8.8 kcal/mol.
The amino acid ASP164
forming (Ionic) bond with
3.34A⁰ distance and -7.9
kcal/mol.
f. Glycitein
The amino acid THR 301 (H-
donor) bond with 2.58 A⁰
distance and energy of -0.9
kcal/mol.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2676| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
g. Malvidin
The amino acid GLY163
form(H-donor) bond with
2.96 A⁰ distance and energy
of -1.6 kcal/mol.
h. Pinocembrin
The amino acid GLY163
forming (H-donor) bond with
2.78A⁰ distance and energy
of -2.6 kcal/mol.
i. Taxifolin
Non-perceptible interactions,
only electrostatics (Van der
Waals) interactions are
perceptible.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2677| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
j. Theaflavin
Both amino acids TYR 268
and THR 301 forming (H-
donor) bonds with a distance
of 2.79 A⁰ and 2.69 A⁰ and
energy -4.5 and -12.8
kcal/mol respectively.
The amino acid ASP164
forming (Ionic) bond with a
distance of 3.77 A⁰ and
energy of -1.0 kcal/mol.
k.Pinocembrin-o-
rhaminosid
The amino acid ASP164
forms two Ionic bonds with
3.27A⁰ and 2.65A⁰ distance
and energy of -2.9 and -7.3
kcal/mol respectively.
The amino acid THR 301
forming (H-donor) bond with
2.97A⁰ distance and energy
of -0.7 kcal/mol.
l.Glycitein-o-
7glucorenoid
One (H-donor) hydrogen
bond by the amino acid
GLU161 with 3.37 A⁰
distance and energy of -0.6
kcal/mol.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2678| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
m. Myricetin3-O-
rhamnoside
The (H-donor) bond formed
by the amino acid TYR 268
with 3.02 A⁰, 2.99 A⁰, and
2.88A⁰ distances and energy
of -0.8, -1.0, and -1.5
kcal/mol respectively.
n.Theaflavin
monogallate
The amino acid GLY 266
forming (H-donor) bond with
2.82 A⁰distance and energy
of -3.4 kcal/mol.
The amino acid TYR 268
forming (π-π) bond with 3.65
A⁰ and energy of -0.0
kcal/mol.
o. Epicatechin-o-
gallate
One (H-donor) bond by the
amino acid GLU167 with
2.86 A⁰ distance and energy
of -5.0 kcal/mol.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2679| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
Table 8: The theoretical binding complex is gained by docking of flavonoids and their derivatives
with SARS COV2 RNA dependent RNA Polymerase(RdRp).
Selected
compounds
2D possible interaction of compounds
Types of binds
a. Kaem
pferol
The (H- donor) hydrogen bonds
formed by the amino acids ASP
760, CYS 622, THR 556, and ARG
553 with distances of 2.9A⁰,
4.31A⁰, 3.03A⁰, and 3.03A⁰ and
energy of -9.3, -0.7, -2.3 and-4.8
kcal/mol respectively.
b. Myricetin
The (H-donor) bonds formed by the
amino acids THR 680, ASP 760,
and THR 556 with distances of
3.21A⁰, 3.02A⁰, and 3.1A⁰ and
energy of -1.4, -2.0, and -2.0
kcal/mol respectively.
c. Naringenin
Two (H-donor) bonds formed by
the amino acids ASP 760 and THR
556 with 3.19 A⁰, 2.72 A⁰, and 3.5
A⁰ distances and energy of -0.8, -
7.5, and -0.6 kcal/mol respectively.
The amino acid THR 680 form(H-
acceptor) bond with 2.86 A⁰
distance and energy of -1.3
kcal/mol.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2680| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
d. Chrysin
There were non-perceptible
interactions, only electrostatics (Van
der Waals) interactions are
perceptible.
e. Epicatechin
Two (H-donor) bonds by the amino
acids TYR 619 and ASP 761 with
2.77A⁰ and 2.82 A⁰ distances and
energy of -9.1 and -3.8 kcal/mol
respectively. And two Ionic bonds
formed by the amino acid ASP760
with 2.98 A⁰ and 2.73 A⁰ distances
and energy of -4.6 and -6.6
kcal/mol respectively.
f. Glycitein
The amino acid ASP760 form 3
bond one (H-donor) bond with
2.81 A⁰ distance and energy of -
3.4kcal/mol. And two ionic bonds
with 3.6 A⁰ and 3.13 A⁰ and energy
of -1.5 and -3.5 kcal/mol
respectively.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2681| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
g. Malvidin
The (H-donor) hydrogen bonds
formed by the amino acids ASP
623 and MET 542 with 2.7A⁰ and
4.11 A⁰ distance and energy of -
6.5 and -4.11 kcal/mol
respectively.
The amino acid ASN 691 form (H-
acceptor) hydrogen bond with 3.08
A⁰ distance and energy of -1.1
kcal/mol.
h. Pinocembrin
The possible interaction of with the
viral protein as shown there is non-
perceptible interaction, only
electrostatics (Van der Waals)
interactions are perceptible.
i. Taxifolin
The amino acid ARG 555 that
forms (H-acceptor) hydrogen bond
with 2.93 A⁰ distance and energy of
-3.6 kcal/mol.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2682| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
j. Theaflavin
(H-donor) bonds formed by the
amino acids ASP 760, TYR 619,
GLU 811, and ASP 623 with a
distance of 3.06 A⁰, 3.41 A⁰, 2.51
A⁰, and 3.4 A⁰ and energy of -2.7,
-0.8, -26.7, and -0.6 kcal/mol
respectively.
Ionic bonds three of this bonds
formed by the amino acids ASP
760 and one by ASP 761 and one
by GLU 811 with a distance of 3.65
A⁰, 3.04 A⁰, 3.25 A⁰, 3.03 A⁰ and
2.51 A⁰ and energy of – (1.4, 4.2,
3.0, 4.3 and 8.7)kcal/mol
respectively.
k. Pinocembri
n-o-
rhaminoside
The amino acid ASP 760 forming
one (H-donor) bond and two Ionic
bonds with distances 2.98 A⁰, 2.76
A⁰, and 3.34 A⁰ and energy of –
(1.9, 6.6 and3.6) kcal/mol
respectively.
l.Glycitein-o-
7glucorenoid
Four (H-donor) bonds formed by
the amino acids ASP 623, TYR 456,
THR 556, and CYS 813, the
distance for the bonds are 3.48 A⁰,
3.01 A⁰, 3.37 A⁰and 4.25 A⁰ with
the energy of – (0.7, 1.1, 0.8 and
0.7 kcal/mol) respectively.
Two (H-acceptor) bonds formed by
the amino acids SER 682 and ARG
624 with a distance of 3.27 A⁰ and
2.8 A⁰ and energy of -0.7 and 2.0
kcal/mol respectively.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2683| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
m. Myricetin 3-
O-rhamnoside
Five (H-donor) bonds formed by the
amino acids ASP 760, THR 556,
and SER 759 with distances of 2.83
A⁰, 2.81 A⁰, 2.87 A⁰, 3.24 A⁰, and
3.09 A⁰, with the energy of – (4.7,
3.7, 5.1,1.4 and 1.9 kcal/mol)
respectively.
n.Theaflavin
monogallate
Two (H-donor) bonds formed by
the amino acids GLU 811 and THR
556 with distances of 2.78 A⁰ and
2.85 A⁰ and energy of -5.0 and -
1.0 kcal/mol respectively.
Two (H-acceptor) bonds formed by
the amino acids THR 680 and ASN
691 with distances of 3.53 A⁰ and
2.99 A⁰ and energy of -0.8 and -
1.7 kcal/mol respectively.
Two ionic bonds formed by the
amino acids ASP 760 and ASP 623
with distances of 3.45 A⁰ and 3.65
A⁰ and energy of -2.1 and -1.4
kcal/mol respectively.
o. Epicatechin-
o-gallate
The two (H-acceptor) bonds by the
amino acids ARG 555 and LYS 545
with distances of 2.96 A⁰ and 3.12
A⁰ and energy of -1.8 and -2.1
kcal/mol respectively.
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2684| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
DISCUSSION
Under the search for any means that can be used
to inhibit or lessen the harmful effect of
Coronavirus, the present study tried to introduce
some commonly available compounds as resources
can help us to face the pandemic. In the current
study, we chose two SARS-CoV2 proteins according
to the extensive study on SARS-CoV2 which show
that there is a multiple of Coronavirus proteins
have been recommended as a possible target for
antiviral drugs like envelope protein, spike protein,
nucleocapsid protein, membrane protein, 3CL
protease, and papain-like protease [10]. One of
the attractive antiviral drug targets is the SARS-CoV
papain-like protease (PLpro) is part of
(nonstructural protein) NSP3, and this papain-like
protease domain is responsible for the release of
NSP1, NSP2, and NSP3 (which are essential for
viral replication) by the hydrolysis of the peptide
bond from the N-terminal region of polyproteins
1a and 1ab, the latter expressed by the first
coronavirus gene (Open Reading Frame 1ab) [21].
Furthermore, the studies showed that SARS-CoV-
PLpro harbors a proteolytic activity by removal of
ISG15 (interferon-induced gene 15) ubiquitin-like
protein as well as ubiquitin (Ub) from proteins of
the host cell, Due to this action, the SARS-CoV2
PLpro enzyme performs a significant role in the
innate immune response during viral infection by
inhibiting the production of cytokines and
chemokines which are responsible for the activation
of the host innate immune response against viral
infection[13,22,23]. In addition to the SARS-CoV2
papain-like protease, the RNA dependent RNA
polymerase is another viral protein also known as
NSP12 catalyzes the synthesis of viral RNA and thus
plays a vital role in the replication and transcription
cycle of COVID-19 virus, possibly with the
assistance of NSP7 and NSP8 as cofactors,
Therefore, NSP12 is considered a primary target
for nucleoside analog antiviral inhibitors such as
Sofosbuvir which acts as a defective substrate for
RNA-dependent RNA polymerase that is essential
for the transcription of Hepatitis C viral RNA and
for its high replicative, and Remdesivir, which
shows potential for the treatment of COVID-19
viral infections [11,12], in our study we try to take
only the NSP12 without the NSP7 or NSP8 or any
compound to examine the direct effect of flavonoid
and their derivatives on RdRp protein.
From our results in Table 5 and 6, we can notice
that the antiviral drug and viral inhibitor reported
very high scores of binding with SARS-CoV2 PLpro
enzyme and RdRp ranging from -6.2 to -8.2
kcal/mol despite that the natural Flavonoids like
Theaflavin as well as the Flavonoids derivatives
gave also high scores some times better than the
antiviral drugs as shown in table 5 and 6. The
Theaflavin and Glycitein 7-O-glucuronide reported
a binding score with PLpro enzyme better than both
the Sofosbuvir and Darunavir antivirus drugs, and
the Theaflavin monogallate has a binding score
with RdRp higher than that of both antiviral drugs,
which means some Flavonoids like Theaflavin and
their derivatives have a high affinity to bind with the
COVID-19 viral protein as reported by (Peterson,
2020) [24]. And that also means consumption of
food or drink which are rich with flavonoids or their
derivatives like black Tea which contains
Theaflavin, Kaempferol, Myricetin, and Quercetin,
etc. can inhibit the viral infection or accelerate
patient cure by inhibiting viral proteins [25].
Additionally, the results in table 6 show that the
Flavonoid derivatives specially glycosylated
flavonoids, for example, Pinocembrin7-O-
Rhamnoside and Myricetin 3-O-Rhamnoside
gained a better binding score with both chosen
COVID-19 viral proteins than the Flavonoids
themselves as shown in Table 7 and 8 and that’s
maybe related to the sugar's moiety (like Rhamnose
which increases the compound's affinity to bind
with viral proteins [26]. And from the Table 7 and 8
can be shown that the other Flavonoids derivatives
like Epicatechin o-gallate, Theaflavin monogallate,
and Glycitein 7-O-glucuronide all these flavonoids
have highly reactive acidic groups like Glucuronic
acid and gallic acid which enable them to binds
with the viral protein tightly, the Glucuronic acid in
some cases work as a minor component in
particular sulfated fucans that isolated from brown
algae and showed a wide variety of biological
activities, such as inhibitors of human pathogenic
viruses including HIV, herpes simplex virus (HSV )
and human cytomegalovirus (HCMV ) [27]. while
The gallate compounds (esters of gallic acid) are
widely employed as antioxidants and other
biological activities mainly the anticancer,
antibacterial, and antifungal properties and anti-
herpes simplex virus (HSV)-2 [28].
CONCLUSION
The docking of some flavonoids and their
derivatives into specific SARS COV2 proteins PLpro
and RdRp form binds in energy scores -which may
exceed the complex energy scores of docking the
antiviral drugs with the same viral proteins-that
enable us to try to use this Flavonoids in COVID-19
treatment also the infected people with COVID-19
virus can consuming nutritions which are rich with
Flavonoids and their derivatives and that can
participate in patients cure of viral infection by
inhibiting of viral proteins.
CONFLICT OF INTEREST
None
Rafeef Amer Abdul – Jabar et al / In-Silico Study of the Inhibitory Effect of Some Flavonoids Compounds
and their Derivatives on SARS-COV-2
2685| International Journal of Pharmaceutical Research | Apr - Jun 2020 | Vol 12 | Issue 2
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