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Article
Potential Inhibitor of COVID-19 Main Protease (Mpro)
from Several Medicinal Plant Compounds by
Molecular Docking Study
Siti Khaerunnisa 1,*, Hendra Kurniawan 2,3, Rizki Awaluddin 4, Suhartati Suhartati5, Soetjipto
Soetjipto 1,*
1 Departement of Medical Biochemistry, Faculty of Medicine, Airlangga University, Surabaya, East Java,
Indonesia, 60132; st.khaerunnisa@fk.unair.ac.id; soetjipto@fk.unair.ac.id
2 Departement of Medical and Surgical Nursing, Faculty of Health Science, University of Muhammadiyah
Jember, Jember, East Java, Indonesia, 68121; hendrakurniawan@unmuhjember.ac.id
3 PhD Student, Tropical Disease Research Center, Faculty of Medicine. Khon Kaen University, Khon Kaen,
Thailand, 40002; hendrakurniawan@unmuhjember.ac.id
4 Departement of Pharmacy, Faculty of Health Science, University of Darussalam Gontor, Ponorogo, East
Java, Indonesia, 63471; awaluddinrizki@gmail.com
5 Departement of Medical Biochemistry, Faculty of Medicine, University of Wijaya Kusuma Surabaya, East
Java, Indonesia, 60225; tati_biokim@yahoo.co.id
* Correspondence: st.khaerunnisa@fk.unair.ac.id ; Tel.: +6281233118194 (S.K.); soetjipto@fk.unair.ac.id;
Tel.: +6281331340518 (S.S.); hendrakurniawan@unmuhjember.ac.id ; Tel.: +628113572277 (H.K.)
Abstract: COVID-19, a new strain of coronavirus (CoV), was identified in Wuhan, China, in 2019.
No specific therapies are available and investigations regarding COVID-19 treatment are lacking.
Liu et al. (2020) successfully crystallised the COVID-19 main protease (Mpro), which is a potential
drug target. The present study aimed to assess bioactive compounds found in medicinal plants as
potential COVID-19 Mpro inhibitors, using a molecular docking study. Molecular docking was
performed using Autodock 4.2, with the Lamarckian Genetic Algorithm, to analyse the probability
of docking. COVID-19 Mpro was docked with several compounds, and docking was analysed by
Autodock 4.2, Pymol version 1.7.4.5 Edu, and Biovia Discovery Studio 4.5. Nelfinavir and lopinavir
were used as standards for comparison. The binding energies obtained from the docking of 6LU7
with native ligand, nelfinavir, lopinavir, kaempferol, quercetin, luteolin-7-glucoside,
demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin,
epicatechin-gallate, zingerol, gingerol, and allicin were -8.37, -10.72, -9.41, -8.58, -8.47, -8.17, -7.99, -
7.89, -7.83, -7.31, -7.05, -7.24, -6.67, -5.40, -5.38, and -4.03 kcal/mol, respectively. Therefore, nelfinavir
and lopinavir may represent potential treatment options, and luteolin-7-glucoside,
demethoxycurcumin, apigenin-7-glucoside, oleuropein, curcumin, catechin, and epicatechin-gallate
appeared to have the best potential to act as COVID-19 Mpro inhibitors. However, further research
is necessary to investigate their potential medicinal use.
Keywords: COVID-2019; Mpro; 6LU7; Medicinal Plant Compounds; Docking
1. Introduction
Coronaviruses (CoVs) are an etiologic agent of severe infections in both humans and animals,
which can cause disorder not only in the respiratory tract but also in the digestive tract and
systemically. Previous studies of CoVs have reported that CoVs can infect certain species of animals,
including mammals, avian species, and reptiles [1].
The new strain of CoV was identified at the end of 2019, initially named 2019-nCoV, and
emerged during an outbreak in Wuhan, China [2]. The Emergency Committee of the World Health
Organization (WHO) declared an outbreak in China on January 30, 2020, which was considered to be
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© 2020 by the author(s). Distributed under a Creative Commons CC BY license.
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a Public Health Emergencies of International Concern (PHEIC) [3]. Officially, WHO named this CoV
COVID-19 (coronavirus disease 2019), on February 11, 2020, based on consultations and
collaborations with the World Organization for Animal Health and the Food and Agriculture
Organization of the United Nations [4].
According to the current situational report from WHO, released on February 11, 2020, 43,103
COVID-19 cases have been confirmed globally, including 2,560 new cases. In China, the number of
confirmed cases reached 42,708, including 2,484 new cases, 7,333 severe cases, and 1,017 deaths.
Outside of China, 395 cases were confirmed in 24 countries, with 1 death [4].
Currently, no specific therapies for COVID-19 are available and investigations regarding the
treatment of COVID-19 are lacking [3]. However, the measures that have been implemented remain
limited to preventive and supportive therapies, designed to prevent further complications and organ
damage [3]. Some preliminary studies have investigated potential combinations that include the
protease inhibitor lopinavir/ritonavir, which is commonly used to treat human immunodeficiency
virus (HIV)/acquired immunodeficiency syndrome patients, for the treatment of COVID-19-infected
patients [5]. Other reported antiviral treatments form human pathogenic CoVs include nucleoside
analogues, neuraminidase inhibitors, remdesivir, umifenovir (arbidol), tenofovir disoproxil (TDF),
and lamivudine (3TC) [5]. A separate investigation performed by Xu et al. (2020) indicated that
among 4 tested drugs (nelfinavir, pitavastatin, perampanel, and praziquantel), nelfinavir was
identified as the best potential inhibitor against COVID-19 Mpro, based on binding free energy
calculations using the molecular mechanics with generalised Born and surface area solvation
(MM/GBSA) model and solvated interaction energy (SIE) methods [6].
The results from preliminary studies remain unapproved for therapeutic use in clinical settings
for the treatment of COVID-19-infected patients [5, 7]. Liu et al. (2020) have successfully crystallised
the main protease (Mpro)/chymotrypsin-like protease (3CLpro) from COVID-19, which has been
structured and repositioned in the Protein Data Bank (PDB) and is accessible by the public. This
protease represents a potential target for the inhibition of CoV replication [6].
Environmental factors can greatly influence the secretion of secondary metabolites from tropical
plants. Therefore, great attention has been paid to the secondary metabolites secreted by plants in
tropical regions that may be developed as medicines [8, 9]. Several compounds, such as flavonoids,
from medicinal plants, have been reported to have antiviral bioactivities [10–12]. In the present study,
we investigated kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin,
apigenin-7-glucoside, oleuropein, curcumin, catechin, epicatechin-gallate, zingerol, gingerol, and
allicin as potential inhibitor candidates for COVID-19 Mpro. The findings of the present study will
provide other researchers with opportunities to identify the right drug to combat COVID-19.
2. Experimental Section
Proteins/Macromolecules
COVID-19 3clpro/Mpro (PDB ID: 6LU7) [13] and 3clpro/Mpro (PDB ID: 2GTB) [6] structures were
obtained from PDB (https://www.rcsb.org/), in .pdb format. PDB is an archive for the crystal
structures of biological macromolecules, worldwide [33].
The 6LU7 protein contains two chains, A and B, which form a homodimer. Chain A was used
for macromolecule preparation. The native ligand for 6LU7 is n-[(5-methylisoxazol-3-
yl)carbonyl]alanyl-l-valyl-n~1~-((1r,2z)-4-(benzyloxy)-4-oxo-1-{[(3r)-2-oxopyrrolidin-3-
yl]methyl}but-2-enyl)-l-leucinamide.
Ligand and Drug Scan
The 3-dimensional (3D) structures were obtained from PubChem
(https://pubchem.ncbi.nlm.nih.gov/), in .sdf format. PubChem is a chemical substance and biological
activities repository consisting of three databases, including substance, compound, and bioassay
databases [34]. Several ligands for which the active compound can be found in herbal medicine were
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downloaded from Dr. Duke’s Phytochemical and Ethnobotanical Databases
(https://phytochem.nal.usda.gov/phytochem/search/list). The compounds used in the present study
were nelfinavir (CID_64143), lopinavir (CID_92727), luteolin-7-glucoside (CID_5280637),
demethoxycurcumin (CID_5469424), apigenin-7-glucoside (CID_5280704), oleuropein
(CID_56842347), curcumin (CID_969516), epicatechin-gallate (CID_107905), zingerol (CID_3016110),
gingerol (CID_442793), catechin (CID_9064), and allicin (CID_65036), quercetin (CID_5280343),
kaempferol (CID_5280863) and naringenin (CID_439246).
Drug-like properties were calculated using Lipinski’s rule of five, which proposes that molecules
with poor permeation and oral absorption have molecular weights > 500, C logP > 5, more than 5
hydrogen-bond donors, and more than 10 acceptor groups [16, 17] Adherence with Lipinski’s rule of
five as calculated using SWISSADME prediction (http://www.swissadme.ch/).
Determination of Active Sites
The amino acids in the active site of a protein were determined using the Computed Atlas for
Surface Topography of Proteins (CASTp) (http://sts.bioe.uic.edu/castp/index.html?201l) and Biovia
Discovery Studio 4.5. The determination of the amino acids in the active site was used to analyse the
Grid box and docking evaluation results. Discovery Studio is an offline life sciences software that
provides tools for protein, ligand, and pharmacophore modelling [18].
Molecular Docking
Ligand optimisation was performed by Avogadro version 1.2, with Force Field type MMFF94,
and saved in .mol2 format. Autodock version 4.2 used for protein optimisation, by removing water
and other atoms, and then adding a polar hydrogen group. Autodock 4.2 was supported by Autodock
tools, MGL tools, and Rasmol. Autogrid then determined the native ligand position on the binding
site by arranging the grid coordinates (X, Y, and Z). Ligand tethering of the protein was performed
by regulating the genetic algorithm (GA) parameters, using 10 runs of the GA criteria. The docking
analyses were performed by both Autodock 4.2, Pymol version 1.7.4.5 Edu and Biovia Discovery
Studio 4.5.
3. Results
Table 1 shows the structures and amino acids found in the active site pockets of 6LU7 and 2GTB.
6LU7 is the main protease (Mpro) found in COVID-19, which been structured and repositioned in PDB
and can be accessed by the public, as of early February 2020.
2GTB is the main protease found in the CoV associated with the severe acute respiratory
syndrome (SARS), which can be accessed in PDB and was suggested to be a potential drug target for
2019-nCov [6]. Xu et al. (2020) mentioned that the main protease in 2019-nCov shares 96% similarity
with that in SARS.
Table 1. Protein target structures and active site amino acids (Biovia Discovery Studio 4.5,
2019) and the native ligand structure
No
PDB
ID
Macromolecule
Native Ligand
Active site
1
6LU7
THR24, THR26, PHE140,
ASN142, GLY143, CYS145,
HIS163, HIS164, GLU166,
HIS172
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2
2GTB
LYS5, ALA7, THR25, HIS41,
MET49, TYR54, VAL125,
TYR126, GLY127, PHE140,
LEU141, ASN142, GLY143,
SER144, CYS145, HIS163,
HIS164, MET165, GLU166,
LEU167, PRO168, HIS172,
ASP187, ARG188, GLN189,
GLN192, ALA198, LYS236,
TYR237, GLN273
Ligands and several drug candidate compounds have been previously selected, based on
adherence to Lipinski’s rule of five. The selected ligands that did not incur more than 2 violations of
Lipinski’s rule could be used in molecular docking experiments with the target protein. The drug
scanning results (Table 2) show that all tested compounds in this study were accepted by Lipinski’s
rule of five.
Table 2. Properties of COVID-19 Mpro potential inhibitor candidates
No
Compound
Molecular
formula
Molecular structure and
Interaction with 6LU7
Lipinski’s rule of five
Properties
Value
1
Lopinavir
C37H48N4O
5
Molecular weight (<500
Da)
628.8
LogP (<5)
4.37
H-Bond donor (5)
4
H-bond acceptor (<10)
5
Violations
1
2
Nelfinavir
C32H45N3O
4S
Molecular weight (<500
Da)
567.78
LogP (<5)
4.33
H-Bond donor (5)
4
H-bond acceptor (<10)
5
Violations
1
3
Luteolin-7-
glucoside
C21H20O11
Molecular weight (<500
Da)
448.38
LogP (<5)
0.16
H-Bond donor (5)
7
H-bond acceptor (<10)
11
Violations
2
4
Demethoxycur
cumin
C20H18O5
Molecular weight (<500
Da)
338.35
LogP (<5)
3
H-Bond donor (5)
2
H-bond acceptor (<10)
5
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Violations
0
5
Apigenin-7-
glucoside
C21H20O10
Molecular weight (<500
Da)
432.34
LogP (<5)
0.55
H-Bond donor (5)
6
H-bond acceptor (<10)
10
Violations
1
6
Oleuropein
C19H22O8
Molecular weight (<500
Da)
378.37
LogP (<5)
1.57
H-Bond donor (5)
3
H-bond acceptor (<10)
8
Violations
0
7
Epicatechin-
gallate
C22H18O10
Molecular weight (<500
Da)
442.37
LogP (<5)
1.23
H-Bond donor (5)
7
H-bond acceptor (<10)
10
Violations
1
8
Catechin
C15H14O6
Molecular weight (<500
Da)
290.27
LogP (<5)
0.85
H-Bond donor (5)
5
H-bond acceptor (<10)
6
Violations
0
9
Curcumin
C21H20O6
Molecular weight (<500
Da)
368.38
LogP (<5)
3.03
H-Bond donor (5)
2
H-bond acceptor (<10)
6
Violations
0
10
Zingerol
C11H16O3
Molecular weight (<500
Da)
196.24
LogP (<5)
1.86
H-Bond donor (5)
2
H-bond acceptor (<10)
3
Violations
0
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11
Gingerol
C17H26O4
Molecular weight (<500
Da)
294.39
LogP (<5)
3.13
H-Bond donor (5)
2
H-bond acceptor (<10)
4
Violations
0
12
Allicin
C6H10OS2
Molecular weight (<500
Da)
162.27
LogP (<5)
1.61
H-Bond donor (5)
0
H-bond acceptor (<10)
1
Violations
0
13
Kaempferol
C15H10O6
Molecular weight (<500
Da)
286,24
LogP (<5)
1,58
H-Bond donor (5)
4
H-bond acceptor (<10)
6
Violations
0
14
Quercetin
C15H10O7
Molecular weight (<500
Da)
302,24
LogP (<5)
1,23
H-Bond donor (5)
5
H-bond acceptor (<10)
7
Violations
0
15
Naringenin
C15H12O5
Molecular weight (<500
Da)
272,25
LogP (<5)
1,84
H-Bond donor (5)
3
H-bond acceptor (<10)
5
Violations
0
Table 3 shows the molecular docking analysis results for several compounds against 6LU7,
including binding energy/Gibbs Energy, ligand efficiency, inhibition constant, intermolecular energy,
and van der Waals (VDW)-H Bond desolvation energy.
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Table 3. Molecular docking analysis of several compounds against 6LU7
Protein
Ligand Properties
Binding
Energy
(ΔG)
Ligand
Efficienc
y
Inhibition
Constant
Intermole
cular
Energy
VDW-H Bond
Desolvation
Energy
6LU7
Native Ligand
-8.37
-0.17
736.89 µM
-14.33
-14.33
Nelfinavir
-10.72
-0.27
13.91 nM
-14.3
-13.83
Lopinavir
-9.41
-0.2
126.76 µM
-14.18
-13.83
Kaempferol
-8,58
-0,41
516,02 nM
-10,07
-9,88
Quercetin
-8,47
-0,39
618,19 nM
-10,26
-10,06
Luteolin-7-
glucoside
-8.17
-0.26
1.03 µM
-11.45
-11.38
Demetoxycurcumin
e
-7.99
-0.32
1.38 µM
-10.68
-10.59
Naringenin
-7,89
-0,39
1,64 uM
-9,09
-8,97
Apigenine-7-
glucoside
-7.83
-0.25
1.81 µM
-10.82
-9.92
Oleuropein
-7.31
-0.27
4.4 µM
-10.59
-10.28
Catechin
-7.24
-0.34
4.95 µM
-9.03
-8.78
Curcumin
-7.05
-0.26
6.82 µM
-10.03
-9.88
Epicatechin-gallate
-6.67
-0.21
13.0 µM
-9.95
-9.51
Zingerol
-5.40
-0.38
112.22 µM
-7.18
-7.1
Gingerol
-5.38
-0.26
113.91 µM
-8.96
-8.82
Allicin
-4.03
-0.45
1.11 mM
-5.52
-5.51
Figure 1. Histogram showing molecular docking results between 6LU7 and several drug candidate
compounds (the binding energy value ΔG is shown in minus kcal/mol)
0
2
4
6
8
10
12
ΔG (-kcal/mol)
Compounds
Native Ligand
Nelfinavir
Lopinavir
Kaempferol
Quercetin
Luteolin-7-glucoside
Demethoxycurcumine
Naringenin
Apigenine-7-glucoside
Oleuropein
Catechin
Curcumin
Epicatechin gallate
Zingerol
Gingerol
Allicin
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Figure 2. Docking analysis visualisation of 6LU7 binding with nelfinavir (A), lopinavir (B), luteolin-
7-glucoside (C), apigenin-7-glucoside (D), oleuropein (E), demethoxycurcumin (F), curcumin (G),
catechin (H), epicatechin-gallate (I), quercetin (J), kaempferol (K) and naringenin (L) using Pymol.
The yellow dots show H-bonds.
Figure 2 (A to I) visualises the binding between 6LU7 and several compounds, including
nelfinavir, lopinavir, luteolin-7-glucoside, apigenin-7-glucoside, oleuropein, demethoxycurcumin,
curcumin, catechin, epicatechin-gallate, quercetin, kaempferol, and naringenin as potential inhibitor
of COVID-19 Mpro.
4. Discussion
Coronaviruses (CoVs) belong to a group of viruses that can infect humans and vertebrate
animals. CoV infections affect the respiratory, digestive, liver, and central nervous systems of humans
and animals [19]. The present study focused on the main proteases in CoVs (3CLpro/Mpro), especially
PDB ID 6LU7, as potential target proteins for COVID-19 treatment. 6LU7 is the Mpro in COVID-19
A
B
C
D
E
F
G
H
I
J
K
L
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that has been structured and repositioned in PDB and has been accessible by the public since early
February 2020. The Mpro of 2019-nCov shares 96% similarity with the Mpro of the SARS-CoV [6, 20].
The Mpro in CoV is essential for the proteolytic maturation of the virus and has been examined as a
potential target protein to prevent the spread of infection by inhibiting the cleavage of the viral
polyprotein [13]. The discovery of the Mpro protease structure in COVID-19 provides a great
opportunity to identify potential drug candidates for treatment.
Proteases represent potential targets for the inhibition of CoV replication, and the protein
sequences of the SARS-CoV Mpro and the 2019-nCoV Mpro are 96% identical, and the active sites in
both proteins remain free from mutations. The Mpro amino acids Thr24, Thr26, and Asn119 are
predicted to play roles in drug interactions [21]. The disruption of protease activity can lead to various
diseases; thus, commonly, host proteases can be used as potential therapeutic targets. In many viruses,
proteases play essential roles in viral replication; therefore, proteases are often used as protein targets
during the development of antiviral therapeutics [22].
Nelfinavir and lopinavir are protease inhibitors with high cytotoxic values against cells infected
with HIV. Lopinavir and ritonavir are protease inhibitors recommended for the treatment of SARS
and MERS, which have similar mechanisms of action as HIV [23]. The antiviral effects of nelfinavir
against CoV have been studied in vitro, in Vero cells infected with SARS-CoV [24]. The IC50 value for
nelfinavir in SARS-CoV is 0.048 µM [25]. In the present study, we used nelfinavir and lopinavir as
drug standards for comparison.
Several compounds, such as flavonoids, from medicinal plants, have been reported to show
antiviral bioactivities [10–12]. We investigated kaempferol, quercetin, luteolin-7-glucoside,
demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin, epicatechin-
gallate, zingerol, gingerol, and allicin as potential inhibitors of the COVID-19 Mpro. An in silico
analysis study showed that the compounds share a similar pharmacophore as nelfinavir. Several
studies have investigated the presence of high numbers of these phenolic compounds belonging
several medicinal plant which abundant in nature (see Table 4).
The binding energies obtained from docking 6LU7 with the native ligand, nelfinavir, lopinavir,
kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenine-7-glucoside,
oleuropein, curcumin, catechin, epicatechin-gallate, zingerol, gingerol, and allicin were -8.37, -10.72,
-9.41, -8.58, -8.47,-8.17, -7.99, -7.89, -7.83, -7.31, -7.05, -7.24, -6.67, -5.40, -5.38, -5.40, and -4.03 kcal/mol,
respectively (see Table 3 and Figure 1).
Table 4. Source of several compounds belong to medicinal plants
Compounds
Sources
Species name
Reference
Kaempferol
Spinach
Spinacia oleracea
[26]
Cabbage
Brassica oleracea
[26]
Dill
Anethum graveolens
[26]
Chinese cabbage
Brassica rapa
[26]
Katuk
Sauropus androgynus
[27]
Quercetin
Dill
Anethum graveolens
[26]
Fennel leaves
Foeniculum vulgare
[26]
Onion
Allium cepa
[26]
Oregano
Oregano vulgare
[26]
Chili pepper
Capsicum annum
[26]
Luteolin-7-glucoside
Olive
Olea Europaea L
[28–30]
Star fruit
Averrhoa belimbi
[31]
Chili pepper
Capsicum annum
[31]
Welsh onion /
Leek
Allium fistulosum
[31]
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Demethoxycurcumine
Turmeric
Curcuma longa
[32], [33]
Curcuma
Curcuma xanthorriza
[32], [33]
Naringenin
Citrus fruit
Citrus sinensis
[34]
Apigenine-7-glucoside
Star fruit
Averrhoa belimbi
[31]
Goji berries
Lycium chinense
[31]
Celery
Apium graveolens
[31]
Olive
Olea Europaea L
[29], [30]
Oleuropein
Olive
Olea Europaea L
[28–30]
Catechin
Green tea
Camellia sinesis
[35–37]
Curcumin
Turmeric
Curcuma longa
[38–41]
Curcuma
Curcuma xanthorriza
[32], [33]
Epicatechin gallate
Green tea
Camellia sinesis
[35–37]
Zingerol
Ginger
Zingiber officiale
[42–44]
Gingerol
Ginger
Zingiber officiale
[42–44]
Allicin
Garlic
Allium sativum
[45–47]
The results of docking analysis (Table 2 and Figure 2) showed that nelfinavir forms H-bonds
with the 6LU7 amino acids Glu166, Gln189, and Gln192 (Figure 2A). Lopinavir forms H-bonds with
the 6LU7 amino acids Glu166, Arg188, and Gln189 (Figure 2B). Luteolin-7-glucoside and forms H-
bonds with the 6LU7 amino acid Phe140, Cys145, His163, His164, and Thr190 (Figure 2C).
Demethoxycurcumin forms H-bonds with the 6LU7 amino acids Phe140, Leu141, Gly143, Ser144,
Cys145, His163, Glu166, and Arg188 (Figure 2D). Apigenin-7-glucoside forms H-bonds with the
6LU7 amino acids Phe140, Cys145, Glu166, Thr190, and Gln192 (Figure 2E). Oleuropein forms H-
bonds with the 6LU7 amino acids Tyr54, Leu141, His163, and Glu166 (Figure 2F). Curcumin forms
H-bonds with the 6LU7 amino acids Leu141, Gly143, Ser144, Cys145, and Thr190 (Figure 2G).
Catechin forms H-bonds with the 6LU7 amino acids His164, Glu166, Asp187, Thr190, and Gln192
(Figure 2H). Epicatechin-gallat forms H-bonds with the 6LU7 amino acids Asn142, His164, Glu166,
and Thr190 (Figure 2I). Quercetin forms H-bonds with the 6LU7 amino acid His164, Glu166, Asp187,
Gln192, Thr190 (Figure 2J). Kaempferol forms H-bonds with the 6LU7 amino acid Tyr54, His164,
Glu166, Apr187, Thr190 (Figure 2J). Naringenin forms H-bonds with the 6LU7 amino acid His164,
Glu166, Asp187, Thr190 (Figure 2J). Docking analysis results, including the H-bonds that interact
with 6LU7 amino acids, can be observed in Table 1. All of the H-bonds interacted with amino acids
in the COVID-19 Mpro active site. The binding energy results are related to the number of H-bonds
formed with the active site pocket of COVID-19 Mpro.
Figure 3. Luteolin-7-glucoside (aglycone) (a) and kaempferol (b) mapped to the pharmacophore
model [48]
(a)
(b)
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Kaempferol and quercetin are a flavonol compounds, while luteolin-7-glucoside is a flavone
within the class of flavonoid compounds [49]. Secondary metabolite compounds are commonly
found in medicinal plants. Luteolin-7-glucoside and kaempferol shown in Figure 3, is a form of
aglycone of flavonoid. Hydroxy groups (-OH), ketone groups (=O) and ether groups (-O-) in luteolin
and kaempferol compounds are predicted to play roles amino acid residue interactions at the active
site of COVID-19 Mpro [50].
The high affinity of drug compounds depends on the type and amount of bonding that occurs
with the active site of the protein. In Table 2, nelfinavir forms many chemical bonds with 6LU7,
including hydrogen bonds and hydrophobic bonds. Kaempferol, quercetin and luteolin-7-glucoside
also forms many chemical bonds, similar to nelfinavir. Therefore, the affinity of kaempferol bonds is
higher compared with other compounds.
The docking analysis in the present study showed the inhibition potential of several compounds,
ranked by affinity (ΔG); nelfinavir > lopinavir > kaempferol > quercetin > luteolin-7-glucoside >
demethoxycurcumin > naringenin > apigenine-7-glucoside > oleuropein > curcumin > catechin >
epigallocatechin > zingerol > gingerol > allicin.
Kaempferol, quercetin, luteolin-7-glucoside, apigenin-7-glucoside, naringenin, oleuropein,
demethoxycurcumin, curcumin, catechin, and epigallocatechin were the most recommended
compounds found in medicinal plants as potential inhibitors of COVID-19 Mpro, which should be
explored in future research.
5. Conclusions
Currently, COVID-19 has emerged in the human population, in China, and is a potential threat
to global health, worldwide. However, no approved drug currently exists to treat the disease. The
currently available drugs for COVID-19 treatment primarily act on the main protease (Mpro). The aim
of this study was to examine several medicinal plant-derived compounds that may be used to inhibit
the COVID-19 infection pathway. Nelfinavir, lopinavir, kaempferol, quercetin, luteolin-7-glucoside,
demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin, and
epicatechin-gallate have the lowest binding energies and inhibition constants. The affinity of
kaempferol bonds is higher compared with other compounds. Therefore, we suggested that
nelfinavir and lopinavir may represent potential treatment options, and kaempferol, quercetin,
luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin,
catechin, and epicatechin-gallate were the most recommended compounds found in medicinal plants
that may act as potential inhibitors of COVID-19 Mpro. However, further research is necessary to
investigate the potential uses of the medicinal plants containing these compounds.
Author Contributions: This study was conducted and conceptualization by SK, HK, RA, SH, SS ,; methodology
by SK, SH and RA,; installation software by RA,; validation by SK and HK,; formal analysis by RA and SS,;
investigation by HK, SH, and SS,; resources by SK and SS,; data curation by SK, HK and RA,; writing-original draft
preparation by SK, HK and RA,; writing-review and editing by SK, HK, RA, SH and SS,; visualization by SK and SS,;
supervision by HK and RA,; project administration by SK,; funding acquisition by SS. All author have read and areed
to the the published version of the manuscript.
Funding: This research was funded by a Grant-in-Aid from Dato’ Sri Prof. Dr. Tahir for this research, through
The Tahir Professorship Program, Indonesia
Acknowledgments: All the authors acknowledge and thank their respective Universities and for Dato' Sri Prof.
Dr. Tahir for all supporting this research.
Conflicts of Interest: The authors declare no conflict of interest.
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