Export the citation:
Patowary, L., Borthakur, M.S. Computational studies of Bridelia retusa phytochemicals for the identification of promising molecules with inhibitory potential against the spike protein and papain-like protease of SARS-CoV-2. Sciences of Phytochemistry 2022, 1(1), 29-41.
Patowary, L, Borthakur, MS. Computational studies of Bridelia retusa phytochemicals for the identification of promising molecules with inhibitory potential against the spike protein and papain-like protease of SARS-CoV-2. Sciences of Phytochemistry. 2022; 1(1):29-41.
Lima Patowary, Malita Sarma Borthakur. 2022. "Computational studies of Bridelia retusa phytochemicals for the identification of promising molecules with inhibitory potential against the spike protein and papain-like protease of SARS-CoV-2" Sciences of Phytochemistry 1, no. 1:29-41.
AI Dimensions Metrics
PlumX Metrics by Elsevier
Computational studies of Bridelia retusa phytochemicals for the identification of promising molecules with inhibitory potential against the spike protein and papain-like protease of SARS-CoV-2Article Access
Views: 696Research Article
In-vitro and in-silico evaluation of Brugmansia sauveolens' ability to treat asthma
by Shouvik Kumar Nandy et al.
Sciences of Phytochemistry; Vol 2, Issue 1
Review
Lawsonia inermis Linn: A breakthrough in cosmeceuticals
by Siuli Sen et al.
Sciences of Phytochemistry; Vol 2, Issue 1
Research Article
by Akinlade Mary Ololade et al.
Sciences of Phytochemistry; Vol 2, Issue 1
Research Article
by Mohammadreza Saeed et al.
Sciences of Phytochemistry; Vol 2, Issue 1
Review
by Nayana Bhuyan et al.
Sciences of Phytochemistry; Vol 2, Issue 1
(clickable & vertically scrollable)
Home / Sciences of Phytochemistry / Volume 1 Issue 1 / 10.58920/sciphy01010029
Research Article
by Lima Patowary, Malita Sarma Borthakur ★
Academic editor: James H. Zothantluanga
Sciences of Phytochemistry 1(1): 29-41 (2022); https://doi.org/10.58920/sciphy01010029
This article is licensed under the Creative Commons Attribution (CC BY) 4.0 International License.
Abstract: SARS-CoV-2 is the pathogen responsible for the on-going COVID-19 pandemic. The two proteins namely, spike protein and papain-like protease are mainly responsible for the penetration and transmission of the virus, respectively. The objective of our study was to find the most promising phytoconstituents of Bridelia retusa that can inhibit both the proteins. Molecular docking, protein-ligand interactions, and molecular dynamics (MD) simulation techniques were used in the study. Bepridil and the co-crystal inhibitors of each protein were used as the standards. All the 14 phytoconstituents along with the standard drug and the co-crystal inhibitor of each protein were subjected to molecular docking. Ten compounds showed better binding affinities than the standards against the spike protein and 7 compounds have shown better binding affinities than the standards against papain-like protease protein. From the protein-ligand interactions, a total of 3 out of 10 for the spike protein and 5 out of 7 for the papain-like protease showed better interactions than the standards. An all-atom MD simulations study revealed that (R)4-(1,5-dimethyl-3-oxo-4-hexenyl)-benzoic acid formed the most stable complex with both proteins. The in-silico study provides an evidence for (R)4-(1,5-dimethyl-3-oxo-4-hexenyl)-benzoic acid as a promising inhibitor of the spike and papain-like protease of SARS-CoV-2. Further investigations such as in-vitro/in-vivo studies are recommended to validate the potency of (R)4-(1,5-dimethyl-3-oxo-4-hexenyl)-benzoic acid.
Severe Acute Respiratory Syndrome (SARS), a viral
respiratory illness, is caused by a coronavirus called SARS-associated
coronavirus (SARS-CoV). SARS-CoV-2 is the virus responsible for the dreadful
infectious coronavirus disease 2019 (COVID-19). The symptoms of COVID-19 are
fever, cough, tiredness, loss of taste and smell, headache, sore throat, aches
& pains, diarrhea, difficulty in breathing, and chest pain. Majority of the
infected people who developed mild to moderate symptoms can recover without
hospitalization whereas medical attention is required in case of serious
symptoms [1]. By the end of 2019, a novel coronavirus designated as SARS-CoV-2
emerged in the city of Wuhan, China, and made an outbreak of unusual viral
pneumonia [2].
To date, a total of 539,119,771 confirmed
cases of COVID-19, of which 6,322,311 deaths have been reported by the World
Health Organisation (WHO) [3]. The SARS-CoV-2 is a member of the beta
coronavirus (beta-CoV) family, which includes RNA viruses with spikes
resembling crowns on the surface of the coronavirus particles, similar to the
SARS (severe acute respiratory syndrome) and MERS (Middle East Respiratory
Syndrome) viruses. However, the WHO estimates that the death rate for
SARS-CoV-2 is between 2 and 3 percent, compared to 14 and 35 percent for SARS
and MERS, respectively. However, the SARS-CoV-2 possesses characteristics such
as rapid person-to-person transmission, asymptomatic transmission, protracted
symptom development, as well as significantly higher fatality rates in the
older population [4].
The pandemic has increased the demand for critical
care, placing enormous strain on the healthcare systems of many nations. Many
therapies were suggested for the treatment of SARS-CoV-2 during the peak COVID-19
pandemic. The WHO has launched a trial, SOLIDARITY, to focus on testing the
four most promising COVID-19 treatments namely, remdesivir, chloroquine and
hydroxy-chloroquine, lopinavir, and lopinavir and ritonavir and
interferon-beta. Chloroquine/hydroxy-chloroquine and lopinavir/ritonavir were
removed from the COVID-19 treatment protocols in June 2020 due to possible
risks and uncertainty of their benefits. Remdesivir was the first and only drug
approved by the FDA on 22 October 2020 [5,6].
However, SARS-CoV-2 kept mutating leading to the emergence
of deadlier variants with higher transmissibility which might weaken the
efficacy of the available vaccines and antiviral medications. Therefore, the search
for novel or adjuvant anti-SARS-CoV-2 medications is urgently required.
Investigating the bioactive compounds of plants appears to be a promising
approach for the identification and development of new medications for COVID-19
[7]. Numerous plants have been reported to possess antiviral phytoconstituents
that may be beneficial against SARS-CoV-2 namely, Lycoris radiata, Artemisia
annua, Pyrrosia lingaua, Lindera aggregate, Isatis indigotica,
Torreya nucifera, Houttuynia cordata, Curcuma longa, and Curcuma
xanthorrhiza [8,9].
Bridelia retusa (L.) A. Juss. is a deciduous tree found throughout
India that grows to be about 20 meters tall. The plant is used as a traditional
herbal remedy. Natives use the stem bark and roots to treat rheumatism and as
astringent agents [10]. During fever, a powdered stem bark mixed with water is
administered [11]. The plant is said to have a variety of biological activities
such as anti-viral, respiratory, cardiovascular, and anticancer activities [12].
In-vivo studies have also revealed that B. retusa has
antinociceptive, anti-inflammatory, antimicrobial, and anti-fungal properties
and also stimulates cell-mediated immunity [13-15]. The facts presented above
supports the rationale for investigating B. retusa phytocompounds as a potential
antiviral agent against SARS-CoV-2. Phytoconstituents like tannins, triterpene
ketone, decanoic acid octadecyl ester, stigmasterol, and dehydrostigmasterol
are found in the bark. The fruits contain β-sitosterol, gallic acid, and
ellagic acid and the leaves contain crude proteins [16].
In our present study, we have selected 14
phytocompounds namely lupeol, friedelin, gallic acid, ellagic acid, (E)-4-(1,5-dimethyl-3-oxo-1,4-hexadienyl)
benzoic acid, (E)-4-(1,5-dimethyl-3-oxo-1-hexenyl) benzoic acid,
(R)-4-(1,5-dimethyl-3-oxo-4-hexenyl) benzoic acid, (-)-isochaminic acid,
(R)-4-(1,5-dimethyl-3-oxohexyl) benzoic acid (ar-todomatuic acid),
5-allyl-1,2,3-trimethoxybenzene (elemicin), (+)-sesamin, β-sitosterol,
stigmasterol, and 4-isopropylbenzoic acid (cumic acid) that have been reported
to be present in B. retusa and were investigated for their inhibitory
potential against the main protease of SARS-CoV-2 through in-silico
approach [17]. In SARS-CoV-2, the spike protein (S) help the virus to penetrate
the host cell [18] and the papain-like protease (PL pro) protein is necessary
for the processing of viral polyproteins to generate a functional replicase
complex and enable the spread of the virus [19]. In the present study, the
inhibitory potential of the selected 14 phytocompounds against these protein
targets will be investigated with in-silico
techniques.
The X-ray crystal structure of
SARS-CoV-2 S-protein (PDB ID: 6M0J) and PL pro (PDB ID: 7OFT) are selected as
the target proteins. They were downloaded in ‘.pdb’ format from the RCSB-PDB
website. The crystal structures of the target chains of the proteins are shown
in Figure 1 and Figure 2. The S-protein was found to have two Chains (Chain A
and Chain E) and the PL pro has only one Chain (Chain A). The co-crystal inhibitor
of the S-protein (2-acetamido-2-deoxy-beta-D-glucopyranose, NAG) and PL pro
protein (p-hydroxybenzaldehyde, HBA) was identified and they manually prepared with
the Chem Draw Professional 16.0.0.82 (68) software.
Figure 1 Chain E of S-protein
Figure 2 Chain A of PL pro
The target proteins
were prepared with the BIOVIA Discovery studio Visualizer v21.1.0.20298
software [20]. The Chain
E (S-protein) and Chain A (PL pro) were used for the study and the other chains
were deleted from the target proteins. The water molecules and heteroatoms were
also removed from the target proteins. Now the polar hydrogen was added to both
the target proteins. Then the active binding sites were defined with the ‘define
and edit binding site’ feature of Discovery Studio Software and active site
coordinates of S-protein (x=-35.41, y=8.55, z=29.13) and PL pro (x= 36.56, y=
9.35, z= 16.36) were saved for future use. The prepared proteins were saved in the
PDB file format for future use.
The structure of the
fourteen phytoconstituents of B. retusa was prepared manually with the
Chem Draw Professional 16.0.0.82 (68) software. These constituents were already
reported as potent against SARS-CoV-2 3CLPro protein [17]. Further, the SMILES ID of the structures was
also saved for future use. The prepared compounds were saved in MDL SD File (*SDF)
format. The structure of the standard drug Bepridil has been obtained from the PubChem
database (PubChem CID 2351)
and it was saved in the *SDF format.
The molecular
docking simulation study (MDSS) was carried out with Autodock Vina on the virtual
screening tool PyRx 0.8 software [21].
The prepared proteins were loaded in the 3D scene in the virtual platform of
the software and converted to the PDBQT file format when made into
macromolecules [22]. The originally
downloaded proteins were reloaded and the unnecessary chains were removed from
the scene except for Chain E (S-protein) and Chain A (PL pro). The sequence of
the amino acids and the co-crystal ligand were revealed on expanding Chain E
and Chain A of the respective proteins. The atoms of the co-crystal ligands
were labeled to determine the accurate location of the co-crystal inhibitors
present at the binding site of the protein. In the Vina search space of the
PyRx 0.8 tool, the pre-defined active binding site coordinates were used to
adjust the alignment of the 3D affinity grid box so that all the amino acids
get covered at the active binding site of the protein. The size of the 3D
affinity grid box was kept at default ay 25 Å. Finally, according to the
standard protocols of the PyRx tool, MDSS were carried out [23].
The 2D interaction
of the phytoconstituents with the best binding affinities with both the
proteins was visualized with the Discovery Studio Visualizer Software. The 2D
ligand interactions of the co-crystal-proteins was also visualized. The
compound that did not form any conventional hydrogen bond with the active site
residues was discarded from the study.
The molecular
dynamics (MD) simulations studies was used to predict the most stable
protein-ligand complex based on the vales of root mean square fluctuation
(RMSF). A protein-ligand complex is considered to be stable if the RMSF value
of all the amino acids is lower than 2.0 Å [24,25]. A protein-ligand complex of each
constituent with S-protein and PL pro were generated and saved in the PDB file
format. The MD simulations was carried out for only proteins along with the
prepared complexes. The MD simulations was performed on the CABS Flex 2.0
server which utilizes the coarse-grained simulations of the protein motion [26]. All the parameters of the
MD simulation study were kept at default.
The
crystal structure of the chain E of ‘S’ protein and chain A of ‘PL Pro’ protein
were retrieved from the RCSB-PDB website, shown in Figure 3 and Figure 4
respectively. The S-protein is made up of two chains, i.e, Chain A (sequence
length 603), and Chain E (sequence length 229). The Chain E of the protein is
complexed with co-crystal inhibitor viz. NAG (2-acetamido-2-deoxy-beta-D-glucopyranose).
The PL pro is composed of one chain, i.e, Chain A (sequence length 315),
complexed with HBA (p-hydroxy benzaldehyde).
Figure 3 Chain E of S-protein with co-crystal ligand
Figure 4 Chain A of papain-like protease with co-crystal ligand
MDSS is an effective
and competent tool for in-silico screening of drug compounds. A docking
study on the PyRx tool can provide a binding affinity value (-kcal/mol) for
each ligand so that the binding potential of ligands toward a protein can be
ranked. The binding affinity of the compounds towards their respective binding
site in the proteins is given in Table 1. For each ligand, the PyRx tool generates
a maximum of 9 binding poses at the active binding site of the target protein.
Table
1
Binding affinity of each drug towards the active binding site of the S-protein
and the PL pro
Drug |
Binding affinity (-kcal/mol) S-protein |
Binding affinity (-kcal/mol) PL pro |
Co-crystal
inhibitor |
4.8 |
6.2 |
Bepridil
(Standard) |
6 |
7.2 |
(-)-Isochaminic
acid |
5.3 |
7.6 |
(+)-
Sesamin |
8.5 |
6.2 |
β-Sitosterol |
7.7 |
6.7 |
Lupeol |
7.7 |
6.2 |
(R)4-(1,5-dimethyl-3-oxo-4-hexenyl)-benzoic
acid |
6.4 |
8.2 |
(E)4-(1,5-dimethyl-3-oxo-1-hexenyl)-benzoic
acid |
6.5 |
7.8 |
(E)4-(1,5-dimethyl-3-oxo-1,4-hexadienyl)-benzoic
acid |
6.7 |
8.4 |
Elemicin |
5.3 |
5.7 |
Stigmasterol |
8.1 |
6.7 |
Gallic
acid |
4.7 |
6.7 |
Friedelin |
8.6 |
6.6 |
Cumic
acid |
5.5 |
7.6 |
Ellagic
acid |
6.3 |
8.3 |
Ar-Todomatuic
acid |
6.1 |
7.8 |
Visualization of the 2D ligand interactions was done with Discovery
Studio Visualizer software. The images of the 2D ligand interactions of the
phytoconstituents with S-protein and PL pro are given in Figure 5 and Figure 6
respectively. The summary of the ligand interactions of each drug with the
amino acids of both the proteins is also given in Table 2 and Table 3.
Figure 5 Visualization of 2D-interaction of S-protein with (A) NAG-(Co crystal), (B) Bepridil, (C) (+)-Sesamin, (D) (E)-4-(1,5-dimethyl-3-oxo-1,4-hexadienyl) benzoic acid, (E)
(E)-4-(1,5-dimethyl-3-oxo-1-hexenyl) benzoic acid, (F) (R)-4-(1,5-dimethyl-3-oxo-4-hexenyl) benzoic acid, (G) Ar-todomatuic acid, (H) β-Sitosterol, (I) Ellagic acid, (J)
Stigmasterol
Table 2 Summary of ligand interaction with the active site of S-protein
Drugs |
Conventional
Hydrogen bond |
Other
interactive sites |
NAG (Co-crystal inhibitor) |
ASN343 (2.61Å) |
LEU368(3.73Å) |
Bepridil |
-- |
PHE342(4.41 Å), LEU368(4.99 Å), SER371(3.71 Å), TRP436(5.02 Å) |
(+)- Sesamin |
-- |
VAL367(3.58Å), PHE374(4.70Å), TRP436(5.26Å,
5.50Å) |
(E)-4-(1,5-dimethyl-3-oxo-1,4-hexadienyl) benzoic
acid |
-- |
PHE342(3.88Å), VAL367 (4.11Å), TRP436 (6.85Å) |
(E)-4-(1,5-dimethyl-3-oxo-1-hexenyl) benzoic acid |
-- |
VAL367, SER373, TRP436 |
(R)-4-(1,5-dimethyl-3-oxo-4-hexenyl) benzoic acid |
CYS336(2.00Å), ASN343(2.59Å), ASP364(1.83Å) |
GLY339(3.64Å), PHE342(4.12Å), ALA363(3.50Å), LEU368(3.95Å), PHE374(4.99Å) |
Ar-todomatuic acid |
ASN343(2.41Å), VAL362(2.71Å), ASP364(1.76Å) |
PHE342(3.93Å), LEU368(3.88Å), PHE374(4.93Å) |
β-Sitosterol |
|
PHE342(4.91Å), LEU368(4.80Å), PHE374(5.24Å) |
Ellagic acid |
CYS336(2.07Å), GLY339(2.22Å) |
VAL367(3.64Å, 4.64Å), LEU368(5.25Å,
5.25Å) |
Stigmasterol |
-- |
PHE342(5.11Å), LEU368(5.08Å), PHE374(5.10Å), TRP436(3.89 Å,
4.62Å) |
Figure 6 Visualization of 2D-interaction of PL Pro-protein with (A) HBA-(Co crystal), (B) Bepridil, (C) (-)-Isochaminic acid, (D) (R)-4-(1,5-dimethyl-3-oxo-4-hexenyl) benzoic acid, (E) (E)4-(1,5-dimethyl-3-oxo-1,4-hexadienyl)-benzoic
acid, (F) (E)-4-(1,5-dimethyl-3-oxo-1-hexenyl)
benzoic acid, (G) Cumic acid, (H) Ellagic acid, (I) Ar-todomatuic acid.
Table 3 Summary of ligand interaction with the active site of PL pro
Drugs |
Conventional
Hydrogen bond |
Other
interactive sites |
HBA (Co-crystal inhibitor) |
VAL11 (2.05Å) |
VAL11(5.17Å), PRO59(5.40Å), TYR72 (4.86Å), LEU80
(4.09Å) |
Bepridil |
-- |
PRO77 (4.14Å), ALA68 (4.37Å, 4.40 Å), THR75
(3.65Å), ARG65 (4.47Å), PRO59 (4.50Å, 5.06Å, 3.44Å), LEU58 (4.36Å) |
(-)-Isochaminic
acid |
-- |
PRO77 (4.46Å), PRO59 (5.29Å), ALA68 (4.48Å),
PHE79 (5.09Å, 5.17Å), TYR72 (5.40Å, 4.07Å), LEU80 (4.21Å) |
(R)4-(1,5-dimethyl-3-oxo-4-hexenyl)-benzoic
acid |
ARG65 (1.91Å) |
ARG65 (4.84Å), PHE79 (5.15Å), PRO59 (3.98Å),
LEU80 (4.10Å), ALA68 (4.25Å), TYR72 (4.21Å), THR75 (3.81Å) |
(E)4-(1,5-dimethyl-3-oxo-1-hexenyl)-benzoic
acid |
-- |
PRO77 (3.73Å), PRO59(4.00Å), VAL11 (4.19Å), LEU80
(3.76Å) |
(E)4-(1,5-dimethyl-3-oxo-1,4-hexadienyl)-benzoic
acid |
ARG65 (1.92Å), LEU80 (2.04Å) |
ARG65 (4.41Å), LEU80 (4.19Å), PRO59 (4.41Å),
ALA68 (4.47Å), THR75(3.74Å), VAL11 (4.97Å), TYR72 (4.26Å) |
Cumic
acid |
ASP76 (1.98Å) |
PHE79 (5.40Å), ALA68 (4.41Å), LEU80 (5.27Å,
5.03Å), PRO59 (4.20Å), TYR56 (5.20Å), TYR72 (4.19Å), TYR83 (4.72Å) |
Ellagic
acid |
LEU80 (1.98Å), THR74 (2.45Å) |
ALA68 (4.12Å, 4.20Å), THR75 (3.83Å), PRO59
(3.57Å, 4.81Å, 3.76Å, 3.93Å), PRO77 (5.23Å, 5.45Å) |
Ar-Todomatuic
acid |
ARG65 (1.96Å, 2.02Å) |
ARG65 (4.62Å), THR75 (3.72Å), ALA68 (4.31Å),
PRO59 (4.42Å), PHE79 (4.89Å), LEU80 (4.33Å), TYR 72 (4.01Å) |
The MD simulation studies performed in the present study generated the
RMSF values for each amino acid residue of the protein thereby furnishing an
idea on the stability of each amino acid under a given set of parameters for a
period of 10 nanoseconds. This study helps to validate the conformational
stability of the protein-ligand complexes. The RMSF plot of the
amino acids of S-protein and PL pro, both alone and in complex with all the
phytoconstituents are given in Figure 7 and Figure 8 respectively.
MDSS is a
computational technique for searching for an appropriate ligand that fits both
energetically and geometrically the binding site of a protein [27]. A more
negative binding affinity value suggests a better binding between a compound
and a protein [23]. A
low binding affinity value also indicates the low energy requirement for
protein-ligand binding [27]. In all cases, the first pose is considered the
best pose since it has the highest binding affinity and the last pose shows the
lowest binding affinity towards the target protein.
Of all the
compounds, 10 phytoconstituents of B. retusa have shown better binding
affinity towards Chain E of the S-protein as compared to the binding affinities
of the standards. These 10 constituents include (+)-Sesamin (-8.5 kcal/mol), (R)4-(1,5-dimethyl-3-oxo-4-hexenyl)-benzoic
acid (-6.4 kcal/mol), (E)4-(1,5-dimethyl-3-oxo-1-hexenyl)-benzoic acid (-6.5 kcal/mol),
(E)4-(1,5-dimethyl-3-oxo-1,4-hexadienyl)-benzoic acid (-6.7 kcal/mol), Stigmasterol
(-8.1 kcal/mol), Friedelin (-8.6 kcal/mol), Ellagic acid (-6.3 kcal/mol), Ar-Todomatuic
acid (-6.1 kcal/mol). Towards Chain A of PL pro, 7 phytoconstituents have shown
better binding affinity than the standards. These include (-)-Isochaminic acid
(-7.6 kcal/mol), (R)4-(1,5-dimethyl-3-oxo-4-hexenyl)-benzoic acid (-8.2
kcal/mol), (E)4-(1,5-dimethyl-3-oxo-1-hexenyl)-benzoic acid (-7.8 kcal/mol), (E)4-(1,5-dimethyl-3-oxo-1,4-hexadienyl)-benzoic
acid (-8.4kcal/mol), Cumic acid (-7.6 kcal/mol), Ellagic acid (-8.3 kcal/mol), Ar-Todomatuic
acid (-7.8 kcal/mol). These phytoconstituents are taken for visualization of
ligand interactions and MD simulations study.
Figure 7 RMSF (Å)
fluctuation plot of all the amino acid residues of Chain E of S-protein alone
and in complex with all the phytoconstituents
Figure 8 RMSF (Å)
fluctuation plot of all the amino acid residues of Chain A of PL pro alone and
in complex with all the phytoconstituents
From the ligand interactions in Figures 5, 6, and Tables 2, and 3
above, it can be observed that for the S-protein, only four out of a total of
sixteen compounds (including standards) has formed a conventional hydrogen bond
with different amino acids at the active site. Bepridil, (+)- sesamin,
(E)-4-(1,5-dimethyl-3-oxo-1,4-hexadienyl) benzoic acid,
(E)-4-(1,5-dimethyl-3-oxo-1-hexenyl) benzoic acid, β-Sitosterol, stigmasterol were not able to form hydrogen bond.
Therefore, the remaining four compounds were taken for further analysis. Similarly, for the PL pro, most of the
phytoconstituents have formed a conventional hydrogen bond with different amino
acids of the active site. The three compounds namely, Bepridil, (-)-isochaminic
acid, and (E)4-(1,5-dimethyl-3-oxo-1-hexenyl)-benzoic acid were not able to
form any hydrogen bond. Therefore, the remaining six phytoconstituents were
taken for the MD simulations study.
For each amino acid, a lower RMSF value indicates limited flexibility
and a higher RMSF value indicates high flexibility in a given system [25]. For the S-protein, the RMSF value for 78.75%
of all the amino acids of the protein without the presence of any ligand was
found to be below 2 Å. For the S-NAG
complex, the RMSF value of a total of 78.75% amino acids was found to be lower
than 2 Å. For the S- (R)-4-(1,5-dimethyl-3-oxo-4-hexenyl) benzoic acid complex,
S- Ar-todomatuic acid complex, S- Ellagic acid complex, 78.75% amino acids have
exhibited RMSF value lower than 2 Å. For the PL Pro protein, without the
presence of any ligand, the RMSF value of a total of 92.18% amino acids was
found to be lower than 2 Å. For PL Pro- HBD complex, the RMSF value of a total
of 92.51% amino acids was found to be lower than 2 Å. For PL Pro- Ellagic acid
complex, the RMSF value of a total of 93.16% amino acids was found to be lower
than 2 Å. For PL Pro- Cumic acid, the RMSF value of a total of 94.46% amino
acids was found to be lower than 2 Å. For PL Pro- Ar-todomatuic acid complex,
the RMSF value of a total of 93.49% amino acids was found to be lower than 2 Å.
For PL Pro- (R)4-(1,5-dimethyl-3-oxo-4-hexenyl)-benzoic
acid complex, the RMSF value of a total of 97.07% amino acids was found to be
lower than 2 Å. For PL Pro- (E)4-(1,5-dimethyl-3-oxo-1,4-hexadienyl)-benzoic
acid complex, the RMSF value of a total of 94.46% amino acids was found to be
lower than 2 Å. The constituents of B. retusa namely, (R)4-(1,5-dimethyl-3-oxo-4-hexenyl)-benzoic
acid, Ellagic acid, Ar-Todomatuic acid were able to form the same stable complexes
similar to that of its co-crystal inhibitors of the S-protein. Phytoconstituents
such as cumic acid, E-4-(1,5-dimethyl-3-oxo-1,4-hexadienyl)-benzoic
acid has been able to form a more stable complex with the PL pro than that of
its co-crystal inhibitor. Of these (R)4-(1,5-dimethyl-3-oxo-4-hexenyl)-benzoic
acid is found to form the most stable complex with PL pro.
Nowadays,
researchers have used new research methods that deviates from the traditional
herbal research. For example, in-silico
techniques such as MDSS and MD simulations have been increasingly applied in
drug discovery research to identify promising phytocompounds for the treatment
of various diseases [17, 28-39]. Medicinal plants are an important source of
clinically important phytocompounds and many pharmaceutical drugs have been developed
from traditional herbal remedies [40-44]. However, some phytocompounds have
poor oral bioavailability. To overcome the bioavailability issues associated
with natural products, novel drug delivery systems have been adopted by many
researchers as the solution [45, 46]. Artificial intelligence, machine
learning, and supervised machine learning have also been utilized in the
process of drug discovery and development [47, 48]. With the advancement in
science, pharmaceutical researchers are using new techniques in drug discovery
programs. In the present study, we have also utilized in-silico techniques that is sustainable, safe, and economical for
the identification of promising bioactive molecules against SARS-CoV-2.
The present in-silico
study has revealed that the phytoconstituent (R)4-(1,5-dimethyl-3-oxo-4-hexenyl)-benzoic
acid of B. retusa is a potential inhibitor of the S-protein and PL pro of the SARS-CoV-2. It has exhibited
better binding affinity towards the active binding site of the S-protein and PL pro in comparison to the
standards. (R)4-(1,5-dimethyl-3-oxo-4-hexenyl)-benzoic
acid has shown similar molecular interactions with that of the standards in the active binding sites of
both the proteins. However, the present study is confined to only the in-silico
model, hence, further, (in-vitro/in-vivo) study is needed to
determine the complete inhibitory potential of the phytocompound against S-protein and PL pro of SARS-CoV-2.
Not applicable
Not applicable
The authors declare no conflicting interests.
Lima Patowary: Study design, molecular docking
simulation study, molecular dynamics simulation study, critical review; Malita
Sarma Borthakur: Molecular docking simulation study, molecular dynamics
simulation study, figures, drafting.
Patowary, L., Borthakur, M.S. Computational studies of Bridelia retusa phytochemicals for the identification of promising molecules with inhibitory potential against the spike protein and papain-like protease of SARS-CoV-2. Sciences of Phytochemistry 2022, 1(1), 29-41.
Patowary, L, Borthakur, MS. Computational studies of Bridelia retusa phytochemicals for the identification of promising molecules with inhibitory potential against the spike protein and papain-like protease of SARS-CoV-2. Sciences of Phytochemistry. 2022; 1(1):29-41.
Lima Patowary, Malita Sarma Borthakur. 2022. "Computational studies of Bridelia retusa phytochemicals for the identification of promising molecules with inhibitory potential against the spike protein and papain-like protease of SARS-CoV-2" Sciences of Phytochemistry 1, no. 1:29-41.
We Computerize Sciences, We Publish Sciences, We Are Scientist