Identification of Compounds from Nigella Sativa as New Potential Inhibitors of 2019 Novel Coronasvirus (Covid-19): Molecular Docking Study

Abstract

The spread of the global COVID-19 pandemic, the lack of specific treatment and the urgent situation requires use of all resources to remedy this scourge. In the present study, using molecular docking, we identify new probable inhibitors of COVID-19 by molecules from Nigella sativa L, which is highly reputed healing herb in North African societies and both Islamic and Christian traditions. The discovery of the Mpro protease structure
in COVID-19 provides a great opportunity to identify potential drug candidates for treatment. Focusing on the main proteases in CoVs (3CLpro/Mpro) (PDB ID 6LU7 and 2GTB); docking of compounds from Nigella Sativa and drugs under clinical test was performed using Molecular Operating Environment software (MOE). Nigelledine docked into 6LU7 active site gives energy complex about -6.29734373 Kcal/mol which is close to
the energy score given by chloroquine (-6.2930522 Kcal/mol) and better than energy score given by hydroxychloroquine (-5.57386112 Kcal/mol) and favipiravir (-4.23310471 kcal/mol). Docking into 2GTB active site showed that α- Hederin gives energy score about-6.50204802 kcal/mol whcih is better energy score given by chloroquine (-6.20844936 kcal/mol), hydroxychloroquine (-5.51465893 kcal/mol)) and favipiravir
(-4.12183571kcal/mol). Nigellidine and α- Hederin appeared to have the best potential to act as COVID-19 treatment. Further, researches are necessary to testify medicinal use of identified and to encourage preventive use of Nigella Sativa against coronavirus infection

Full text

doi.org/10.26434/chemrxiv.12055716.v1
Identification of Compounds from Nigella Sativa as New Potential
Inhibitors of 2019 Novel Coronasvirus (Covid-19): Molecular Docking
Study.
Salim Bouchentouf, Noureddine Missoum
Submitted date: 31/03/2020 • Posted date: 02/04/2020
Licence: CC BY-NC-ND 4.0
Citation information: Bouchentouf, Salim; Missoum, Noureddine (2020): Identification of Compounds from
Nigella Sativa as New Potential Inhibitors of 2019 Novel Coronasvirus (Covid-19): Molecular Docking Study..
ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.12055716.v1
The spread of the global COVID-19 pandemic, the lack of specific treatment and the urgent situation requires
use of all resources to remedy this scourge. In the present study, using molecular docking, we identify new
probable inhibitors of COVID-19 by molecules from Nigella sativa L, which is highly reputed healing herb in
North African societies and both Islamic and Christian traditions. The discovery of the Mpro protease structure
in COVID-19 provides a great opportunity to identify potential drug candidates for treatment. Focusing on the
main proteases in CoVs (3CLpro/Mpro) (PDB ID 6LU7 and 2GTB); docking of compounds from Nigella Sativa
and drugs under clinical test was performed using Molecular Operating Environment software (MOE).
Nigelledine docked into 6LU7 active site gives energy complex about -6.29734373 Kcal/mol which is close to
the energy score given by chloroquine (-6.2930522 Kcal/mol) and better than energy score given by
hydroxychloroquine (-5.57386112 Kcal/mol) and favipiravir (-4.23310471 kcal/mol). Docking into 2GTB active
site showed that α- Hederin gives energy score about-6.50204802 kcal/mol whcih is better energy score given
by chloroquine (-6.20844936 kcal/mol), hydroxychloroquine (-5.51465893 kcal/mol)) and favipiravir
(-4.12183571kcal/mol). Nigellidine and α- Hederin appeared to have the best potential to act as COVID-19
treatment. Further, researches are necessary to testify medicinal use of identified and to encourage preventive
use of Nigella Sativa against coronavirus infection.
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1
Identification of Compounds from Nigella Sativa as New Potential Inhibitors of 2019
Novel Coronasvirus (Covid-19): Molecular Docking Study.
Bouchentouf Salim1,2,* and Missoum Noureddine2,3
1: Facult of Technology, Doctor Tahar Moulay University of Saida, Algeria
*bouchentouf.salim@yahoo.fr , salim.bouchentouf@univ-saida.dz
2: Laboratory of Natural products and Bioactives, University of Tlemcen
3: Faculty of Technology, University Hassiba Ben Bouali of Chlef, Algeria
Abstract
The spread of the global COVID-19 pandemic, the lack of specific treatment and the urgent situation
requires use of all resources to remedy this scourge. In the present study, using molecular docking, we
identify new probable inhibitors of COVID-19 by molecules from Nigella sativa L, which is highly reputed
healing herb in North African societies and both Islamic and Christian traditions. The discovery of the Mpro
protease structure in COVID-19 provides a great opportunity to identify potential drug candidates for
treatment. Focusing on the main proteases in CoVs (3CLpro/Mpro) (PDB ID 6LU7 and 2GTB); docking of
compounds from Nigella Sativa and drugs under clinical test was performed using Molecular Operating
Environment software (MOE). Nigelledine docked into 6LU7 active site gives energy complex about -
6.29734373 Kcal/mol which is close to the energy score given by chloroquine (-6.2930522 Kcal/mol) and
better than energy score given by hydroxychloroquine (-5.57386112 Kcal/mol) and favipiravir (-4.23310471
kcal/mol). Docking into 2GTB active site showed that α- Hederin gives energy score about-6.50204802
kcal/mol whcih is better energy score given by chloroquine (-6.20844936 kcal/mol), hydroxychloroquine (-
5.51465893 kcal/mol)) and favipiravir (-4.12183571kcal/mol). Nigellidine and α- Hederin appeared to have
the best potential to act as COVID-19 treatment. Further, researches are necessary to testify medicinal use of
identified and to encourage preventive use of Nigella Sativa against coronavirus infection.
Keywords: COVID-19, Nigella Sativa, 6LU7, 2GTB, molecular docking, MOE software.
Introduction
During December 2019 a novel coronavirus (COVID-19) has been reported from Hubei province in Chinai.
The virus associated with human to human transmission is causing several human infections and disorder
not only in the respiratory apparatus but also in the digestive tract and systemically ii iii iv. On March 11,
2020, world health organization characterizes COVID-19 as a pandemic which caused until 30, March, 2020
30,105 death and 638,146 confirmed cases over the worldv. Due to gravity of the situation, urgent and
complementary efforts from researchers are necessary to find therapeutic agents and new preventive
methods. Description of COVID-19 virus shown three important proteins know as papain-like protease
(PLpro), 3C-like protease (3CLpro) and spike protein to be attractive target for drug developmentvi. Viral
polypeptide onto functional proteins is processed by Coronavirus PLpro which is also a deubiquitinating
enzyme that can dampen host anti-viral response by hijacking the ubiquitin (Ub) systemvii viii. It has been
shown also that SARS-3CLpro is a cysteine protease indispensable to the viral life cycle ix . Angiotensin-
converting enzyme 2 (ACE2) is used by Coronavirus spike protein as a receptor to help the virus enter cells
x .The potential target (Mpro)/chymotrypsin-like protease (3CLpro) from COVID-19 (6LU7) have been
successfully crystallized by Liu et al (2020) and repositioned in Protein Data bank (PDB)xi. Medicinal
chemists are focusing also on the main protease of SARS-Coronavirus (2GTB) to develop antiviral
treatments of the virus causing COVID-19xii because it shares 96 % similarityxiii. Some in silico preliminary
studies have been conducted to find small molecules from herbal plants with the potential to inhibit 2019
novel coronavirus xiv xv xvi.

2
Contagious disease treatment and control is widely demonstrated by effectiveness of medicinal herbs xviixviii
xix xx xxi. Absence of specific therapy for COVID-19 leads population over many regions in the world to use
medicinal herbs knows in ethnophamacologie as antiviral. In our present study and inspired by recent
molecular docking studies xxii xxiii we illustrate interactions between small molecules from North African
medicinal herb; Nigella sativa L in order to identify the favorable molecules for COVID-19 treatment and
compare them to proposed drugs such as chloroquine hydroxychloroquine,azithromycin, arbidol, remdesivir,
and favipiravir xxiv xxv. The in silico study was done using Molecular Operating Environment software
(MOE)xxvi. The present study will provide other researchers with important investigation way to identify
new COVID-19 treatment and use of natural products.
Material and methods
Medicinal herb choice
Based on local survey we reported that Nigella sativa L. commonly known as black seed or black cumin
(Haba sawda) is widely recommended in society during the COVID-19 crisis for their probable antiviral
effects. The large traditional use of black cumin as panacea (universal healer) in North African societies
came from Islamic belief and also Bible xxvii. Nigella sativa is cited by many research papers for its multiple
benefits as antiviral, anti-inflammatory, anti-cancer, analgesic…etc xxviii xxix xxx xxxi.
Preparation of both enzymes and ligands
Download of 3clpro/Mpro COVID-19 and 3clpro/Mpro SARS-coronavirus three dimensional structures were
done from Protein Data Bankxxxii under PDB ID 6LU7 and 2GTB respectivelyxxxiii xxxiv. Crystallographic
properties of 6LU7 and 2GTB are reported in table 1. Table 2 reports major chemical compounds of Nigella
sativa L collected from literature xxxv xxxvi xxxvii xxxviii xxxix xl. The 3-dimensional (3D) structures of main
chemical compounds from Nigella sativa were downloaded in .sdf format from PubChemxli. Lipinski’s
physicochemical parameters rule xlii xliii xliv were also studied for each ligand and reported in table 3.
Chemical structures of main drugs under clinical tests for treatment of COVID-19 are reported in table 4 xlv
xlvi xlvii.
Identification of the preferred region of the receptor that interacts with ligands is known by active site
prediction and isolation protocolxlviii. Using Hamiltonian AM1 (Austin model 1) implanted in MOE and field
strengths in the MMFF94x (Merck molecular force field) energy of the protein was minimized. In addition,
water molecules were removed from the protein surface so that the interaction region will not be hidden
while docking. By use of site-finder module implanted in MOE, active sites of 6LU7 and 2GTB were
identified and shown in figure 1 and 2 respectively. Also both natural ligands (compounds from Nigella
sativa L ) and proposed drugs were submitted to energy minimizing under default conditions of temperature
= 300°K and pH = 7.
Table 1: Crystallographic properties of enzymes
Enzyme
PDB
Code
Classification
Organism
Expression
system
Resolution
Method
Total
structure
weight
(DA)
chaine
COVID-19
main
protease
6LU7
VIRAL
PROTEIN
Bat SARS-
like
coronavirus
Escherichia
coli
BL21(DE3)
2.1 Å
X-RAY
DIFFRACTION
34506.34
A
SARS
coronavirus
main
peptidase
2GTB
HYDROLASE
SARS
coronavirus
CUHK-L2
Escherichia
coli
2 Å
X-RAY
DIFFRACTION
34649.48
A

3
Table 2: Chemical structures of major compounds from Nigella Sativa.
Nigellicine
Nigellidine
Nigellimine
Carvacrol
α- Hederin
6- Thymol
Thymoquinone
Dithymoquinone
thymohydroquinone
Table 3: Expanded Lipinski’s physicochemical parameter for Nigella sativa compounds.
N°
Ligands
Molecular
weight
(g/mol)
Toxicity
Retro
synthese
%
Hdonn
Hacc
Log
P
Log
S
TPSA
(Å2)
1
Nigellicine
246.27
no
33.33
1
3
1.06
-2.19
60.85
2
Nigellidine
294.35
no
100
1
2
2.94
-3.7
43.78
3
Nigellimine
203.24
no
100
0
3
2.56
-2.42
31.35
4
Carvacrol
150.22
no
100
1
1
2.82
-2.69
20.23
5
α- Hederin
750.97
no
35.85
7
12
3.52
-8.24
195.60
6
Thymol
150.22
no
100
1
3
2.82
-2.69
20.23
7
Thymoquinone
164.20
no
100
0
2
1.67
-2.48
34.14
8
Dithymoquinone
328.41
no
0.00
0
4
2.71
-3.90
68.28
9
thymohydroquinone
166.22
no
100
2
2
2.53
-2.01
40.46

4
Table 4: Chemical structures of main proposed drugs for COVID-19 treatment
ligands
Name
Structures
Pub Chem CID
Expanded Lipinski’s rule
1
Chloroquine
2719
Properties
Value
MW(g/mol)
320.89
H-donor
2
H-acceptor
1
LogP
3.39
LogS
-3.76
TPSA (Å)
29.36
2
Hydroxychloroquine
3652
Properties
Value
MW(g/mol)
336.89
H-donor
3
H-acceptor
2
LogP
2.37
LogS
-3.23
TPSA (Å)
49.59
3
Azythromycine
447043
Properties
Value
MW(g/mol)
751.01
H-donor
7
H-acceptor
11
LogP
-0.93
LogS
-3.64
TPSA (Å)
182.48
4
Arbidol
131411
Properties
Value
MW(g/mol)
477.42
H-donor
1
H-acceptor
3
LogP
6.07
LogS
-5.82
TPSA (Å)
54.70
5
Remdesivir
121304016
Properties
Value
MW(g/mol)
602.58
H-donor
4
H-acceptor
10
LogP
1.24
LogS
-5.17
TPSA (Å)
203.01
6
Favipiravir
492405
Properties
Value
MW(g/mol)
157.10
H-donor
2
H-acceptor
3
LogP
-1.19
LogS
-1.33
TPSA (Å)
84.55

5
Figure 1: Isolated active site of 6LU7 in complex with an inhibitor N3 (PRD_002214)
Figure 2: Isolated active site of SARS coronavirus main peptidase (PDB 2GTB) inhibited by an aza-peptide
epoxide
Docking and Building Complexes
Docking using Dock module implanted in MOE, consists of positioning ligands into active site of 6LU7 and
2GTB with most of default tools to predict how molecules interacts with the binding site of the receptor xlix l
li . First docked molecules series were proposed drugs and respective reference inhibitors (PRD_002214 of
6LU7 and AZP for 2GTB) in order to compare obtained score with score from chosen ligands of Nigella
sativa L. Table 5 gives obtained scores by drugs under clinical test and inhibitor ligands (PRD_002214 and
AZP). Table 6 shows scores of second docked ligand series from compounds from Nigella Sativa.
Table 5: Obtained docking score by drugs under clinical test and inhibitors.
ligand
molecules
Score (Kcal/mol)
Reference
ligand
6LU7
2GTB
PRD_002214
-10.4669304
/
AZP
/
-7.49913883
1
Chloroquine
-6.2930522
-6.20844936
2
Hydroxychloroquine
-5.57386112
-5.51465893
3
Azythromycine
-5.57062292
-6.25860453
4
Arbidol
-7.15007734
-6.74997902
5
Remdesivir
-6.35291243
-7.07897234
6
Favipiravir
-4.23310471
-4.12183571

6
Table 6: Obtained score from docking of Nigella Sativa compounds with 6LU7 and 2GTB
Ligand
Score (kcal/mol)
6LU7
2GTB
Nigellicine
-5.11696768
-5.05794954
Nigellidine
-6.29734373
-5.58170891
Nigellimine
-4.80306292
-5.07316256
Carvacrol
-4.8290143
-4.45325089
α- Hederin
-5.25583553
-6.50204802
Thymol
-4.50417519
-4.03594398
Thymoquinone
-4.71068573
-4.41701126
Dithymoquinone
-4.45150137
-4.99905396
thymohydroquinone
-4.22977924
-4.23156166
Results and discussion
Obtained results showed that Nigellidine gives the lowest energy (-6.29734373 Kcal/mol) in complex with
6LU7, which is the best score when compared to other docked compounds. Nigellidine gives score close to
the one given by chloroquine (-6.2930522 Kcal/mol) and better score than hydroxychloroquine (-
5.57386112 Kcal/mol) and favipiravir (-4.23310471 kcal/mol). Nigellidine in complex with 6LU7 (Figure
3A and 3B) shows two hydrogen possible interactions with amino acid MET49 (H-donor) with a distance
about 4.25Å and energy of -0.7Kcal/mol and π-H interaction with amino acid THR190 with a distance about
4.24Å and energy of -1.3Kcal/mol. Interactions between the rest of compounds from Nigella sativa and
6LU7 are reported in table 7.
Figure 3A: 2D diagram interaction between
Nigellidine and 6LU7
Figure 3B: 3D diagram interaction between
Nigellidine and 6LU7
Docking results with 2GTB show that α- Hederin gives better score (-6.50204802 kcal/mol) than
chloroquine (-6.20844936 kcal/mol), hydroxychloroquine (-5.51465893 kcal/mol)) and favipiravir (-
4.12183571kcal/mol). Alpha-hedrin in complex with 2GTB (figure 4A and 4B) show that only one
hydrogen interaction (H-acceptor) with amino acid Gly 143 is possible with distance about 2.92 Å and
energy of -2.2 Kcal/mol.. Interactions between the rest of compounds from Nigella sativa and 2GTB are
reported in table 9.
Figure 4A: 2D diagram interaction between α-
hederin and 2GTB
Figure 4A: 3D diagram interaction between α-
hederin and 2GTB

7
Table 7: Interactions and 2D diagrams of compounds from Nigella Sativa with 6LU7
Ligand
Structure interactions
Type of interactions
Nigellicine
Two hydrogen interaction are possible
with:
- Amino acid THR 190 (H-donor) with
distance about 3.11 Å and energy of -3.3
Kcal/mol.
- Amino acid GLU 166 (π-H) with
distance about 4.12 Å and energy of -1.0
Kcal/mol
Nigellimine
No perceptible interactions, only
electrostatics exist (Van der Waals)
Carvacrol
Three hydrogen interactions are possible
with:
- Amino acid HIS 41 (H-π) with
distance about 4.35 Å and energy of -0.6
Kcal/mol.
- Amino acid GLN 189 (π-H) with
distance about 4.16 Å and energy of -0.8
Kcal/mol.
- Amino acid THR 190 (π-H) distance
about 4.67 Å and energy of -0.8
Kcal/mol
α- Hederin
Three hydrogen interaction are possible
with:
- Amino acid HIS 164(H-donor) with
distance about 2.83 Å and energy of -1.8
Kcal/mol.
-Amino acid CYS 145 with distance
about 4.08 Å and energy of -1.1
Kcal/mol.
- Amino acid MET 165 distance about
3.73 Å and energy of -0.6 Kcal/mol

8
Thymol
Only one hydrogen interaction (π-H) is
possible with amino acid GLN189 with
distance about 4.24 Å and energy of -0.7
Kcal/mol.
Thymoquinone
Only one hydrogen interaction (π-H) is
possible with amino acid THR 190 with
distance about 4.70 Å and energy of -0.8
Kcal/mol.
Dithymoquinone
Only one hydrogen interaction (H-
acceptor) is possible with amino acid
THR 190 with distance about 2.89 Å and
energy of -3.9 Kcal/mol.
Thymohydroquinone
Only one hydrogen interaction (π-H) is
possible with amino acid GLU 166 with
distance about 4.46 Å and energy of -1.0
Kcal/mol.

9
Table 8: Interactions and 2D diagrams of compounds from Nigella sativa with 2GTB
Ligand
Structure interactions
Type of interactions
Nigellicine
Three hydrogen interaction are
possible with:
- Amino acid CYS 145 (H-donor)
with distance about 3.91 Å and
energy of -0.7 Kcal/mol.
- Amino acid GLY 143 (H-acceptor)
with distance about 3.04 Å and
energy of -2.2 Kcal/mol.
- amino acid CYS 145 (H-acceptor)
distance about 3.51 Å and energy of
-1.4 Kcal/mol
Nigellidine
Only one hydrogen interaction (H-
acceptor) is possible with amino
acid HIS 163 with distance about
3.01 Å and energy of -11.6
Kcal/mol.
Nigellimine
Only one hydrogen interaction (π-π)
is possible with amino acid HIS 41
with distance about 3.95 Å.
Carvacrol
There are non-perceptible
interactions, only electrostatics (Van
der Waals) interactions are
perceptible.

10
Thymol
There are non-perceptible
interactions, only electrostatics (Van
der Waals) interactions are
perceptible.
Thymoquinone
There are non-perceptible
interactions, only electrostatics (Van
der Waals) interactions are
perceptible.
Dithymoquinone
There are non-perceptible
interactions, only electrostatics (Van
der Waals) interactions are
perceptible.
Thymohydroquinone
Only one hydrogen interaction (H-
acceptor) is possible with amino
acid GLY143 with distance about
3.20 Å and energy of -0.7 Kcal/mol.
Conclusion
The aim of the present study is to identify molecules from natural products which may inhibit COVID-19 by
acting on the main protease (Mpro). Obtained results by molecular docking showed that Nigellidine and α-
hederin are main compounds from Nigella sativa which may inhibit COVID-19 giving the same or better
energy score compared to drugs under clinical tests. Those results encourage further in vitro and in vivo
investigations and also encourage traditional use of Nigella sativa preventively.

11
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