Hindawi

Applied Bionics and Biomechanics

Volume 2022, Article ID 5997895, 8 pages
https://doi.org/10.1155/2022/5997895

Research Article
The Mechanism of Osthole in the Treatment of Gastric Cancer
Based on Network Pharmacology and Molecular
Docking Technology

Yunjie Ju
Medical College of China Three Gorges University, China Three Gorges University, Yichang 443002, China

Correspondence should be addressed to Yunjie Ju; 2018128116@ctgu.edu.cn

Received 28 February 2022; Revised 25 March 2022; Accepted 30 March 2022; Published 21 April 2022

Academic Editor: Fahd Abd Algalil

Copyright © 2022 Yunjie Ju. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. To study the mechanism of osthole in GC based on network pharmacology and molecular docking. Methods. The
potential targets of osthole were predicted through the TCM System Pharmacology Analysis Platform, SwissTargetPrediction,
and PharmMapper database. Targets related to gastric cancer were obtained through OMIM and GeneCard database. The
online tool Venny 2.1.0 was used to screen GC and common target of osthole. The targets after the intersection of drugs and
diseases were entered into the STRING database, and the protein interaction network was constructed, and the core targets
with high correlation were screened out. The WebGestalt website was used to GO functional enrichment and KEGG pathway
analysis and visualization with KOBAS website. The Cytoscape 3.8.2 was employed to draw the C-T-P-D (compound–target–
pathway–disease) network visualization diagram. Finally, molecular docking validation was performed using PyMOL 2.5 and
Discovery Studio Standalone. Results. Through prediction and screening, 108 corresponding targets were screened from
osthole, and 173 targets were obtained after intersecting with gastric cancer targets. Among them, the top ten targets were the
core targets of this study, including MAPK3, MAPK1, SRC, AKT1, HSP90AA1, RXRA, ESR1, RELA, MAPK14, and EGFR.
The analysis of GO, KEGG, and PPI showed that the mechanism of action of osthole against GC may be closely related to the
regulation of the PI3K signaling pathway. The results of molecular docking showed that osthole had a good affinity with
MAPK3, which is a crucial part of the PI3K signaling pathway. Conclusion. This study preliminarily revealed the targets and
related pathways of osthole in the treatment of gastric cancer and provided a new idea for further exploration of osthole
targeted prevention and treatment of gastric cancer.

1. Introduction escaped tumor cells will proliferate and metastasize again,

Gastric cancer (GC) is one of the common malignant
tumors in clinic, which seriously threatens people’s life and
health. In most countries, gastric cancer occurs in the main
part of the stomach (the corpus) and has high morbidity
and mortality worldwide. The carcinogenesis of GC is a mul-
tistep and multistage development process involving Helico-
bacter pylori infection, geographic location, and other risk
factors [1, 2]. Surgical resection is the mainstay of treatment
for GC. However, 60% of GC patients will relapse within 2 to
3 years after surgery or chemotherapy, because the shed and
while chemotherapy drugs lack sensitivity to most adenocar-
cinomas, and are often caused by drug resistance [3]. There-
fore, novel effective drugs for GC therapy need to be
developed.
Osthole is the main pharmacological active component
of Chinese medicine Cnidium, which belongs to natural cou-
marin. Studies have shown that osthole has physiological
and pharmacological effects such as osteogenesis, immune
regulation, neuroprotection, and antioxidant functions
[4–6]. It also has inhibitory effects on a variety of cancers,
such as lung cancer [7, 8], sarcoma [9], glioma [10],
2 Applied Bionics and Biomechanics

leukemia [11], and hepatocellular carcinoma [12]. However,

few studies have researched the mechanisms and the treat- Osthole Gastric cancer
ment of osthole on GC.
Network pharmacology provides a new network model
of “multitarget, multipath, and multilink,” which has
become an indispensable method for exploring the potential Targets of component Target fishing
(TCMSP, Swisstarget prediction, (GeneCards, OMIM
mechanism of medicines [13]. It integrates the technology
PharmMapper) database)
and knowledge of multiple disciplines, such as systems biol-
ogy, bioinformatics, and pharmacology, and can build a
drug–target–pathway–disease network. Recently, network
pharmacology is frequently used to predict related targets, Common targets
pathways in cancers closely related to signal transduction, collecting
such as gastric cancer [13, 14]. Molecular docking is based
on computer simulation technology. It simulates the geo-
metric structure of molecules and the forces between mole-
cules through chemometric methods, studies the PPI network construction
interactions between molecules, and finds the process of
low-energy binding modes between ligands and receptors.
This study systematically analyzed the potential targets of
osthole for GC, predicted its anti-GC pathway and biological GO analysis
process information, conducted molecular docking to verify KEGG analysis
the results, and explored the antitumor potential of osthole.
The molecular mechanism provides a theoretical basis for
the use of osthole in treating GC. The schematic diagram
of the research process of osthole against gastric cancer is C-T-P-D network construction
shown in Figure 1.

2. Materials and Methods

2.1. Fishing of Computational Targets. The compound struc-
ture of osthole (Figure 2(a), CAS:484-12-8) was accessed
from PubChem. Meanwhile, the targets of osthole were
obtained from the TCMSP database (http://tcmsp-e.com/),
SwissTargetPrediction (http://www.swisstargetprediction
.ch/), and PharmMapper (lilab-ecust.cn) and combined with
literature to supplement the drug targets. On the other hand,
use the GeneCards (https://www.genecards.org/) database
and OMIM (https://omim.org/) database to obtain GC tar-
gets, select the species as “Homo sapiens,” and enter “Gastric
Cancer” to retrieve GC-related genes. The online tool Venny
2.1.0 was used to analyze the common targets of GC and ost-
hole and draw a Venn diagram.
2.2. The PPI Network Construction. The common genes
obtained by mapping drugs and diseases are in STRING
(https://string-db.org/) platform for PPI network analysis,
and the option was restricted to “Homo sapiens,” and the
isolated targets were removed and screened with a high con-
fidence level (0.95) to obtain the PPI network. Then, the PPI
network was imported into Cytoscape 3.6.3; topological
analysis was performed by the Cytohubba tool. According
to the order of degree value, the most closely related targets
(the top 10) were selected as the core targets of osthole anti-
GC.
2.3. Gene Function and Pathway Enrichment Analysis. The
Webgestalt (http://www.webgestalt.org/) and KOBAS
(http://kobas.cbi.pku.edu.cn/) were used for GO enrichment
analysis and KEGG pathway analysis. The core targets were
Molecular
docking
Figure 1: Network pharmacology workflow of osthole.
imported, set the analyzed species as “Homo sapiens,” and
the significance level P value < 0.05. These functions with
a high significance level and a large frequency proportion
will be considered as the potential biological functions of
osthole against gastric cancer. The ImageGP (http://www
.ehbio.com/ImageGP) website was employed to draw
advanced bubble charts.
2.4. Construction and Analysis of Compound–Target–
Pathway–Disease Network. To understand the complex rela-
tionships among C-T-P-D, we used Cytoscape 3.8.2 to build
and analyze networks, visualizing them based on underlying
data.
2.5. Molecular Docking Analysis. Molecular docking verifica-
tion was performed on the top ten core targets of osthole
against gastric cancer. Download compound mol2 format
at Traditional Chinese Medicine Database@Taiwan (http://
tcm.cmu.edu.tw/zh-tw/). Select the crystal structure of the
target protein with high resolution (A) and complete struc-
ture from the PDB database (https://www.rcsb.org/) and
download it. Use AutoDock Tools 1.5.6 to delete the water
molecule of the target protein and add nonpolar sexual
hydrogen and calculate Gasteiger charge; all flexible bonds
are rotatable by default and save as pdbqt format file as
Applied Bionics and Biomechanics 3

Osthole GC

O O O
15 173 11963
(0.1%) (1.4%) (98.5%)

(a) (b)

Figure 2: (a) The chemical structure of osthole. (b) Venn diagram of potential targets of osthole in the treatment of GC.

Figure 3: Protein interaction network of osthole and gastric cancer.

4 Applied Bionics and Biomechanics
RELA 18
ESR1 18
MAPK8 18
EGFR 22
RXRA 25
HSP90AA1 26
AKT1 28
SRC
MAPK3
MAPK1
0 5 10 15 20 25 30
Score
(a)
Figure 4: (a) The top 10 effective targets were ranked by degree value. (b) The color based on the degree of connectivity of the nodes.
docking ligand. Run AutoDock Vina 1.1.2 software for dock-
ing and calculate the docking score and use Pymol software
for visualization.
3. Results
3.1. Target Fishing. We obtained 91, 100, and 260 targets
from the TCMSP database, SwissTargetPrediction, and
PharmMapper, respectively. After merging and deduplica-
tion, a total of 188 drug-related targets were obtained. Mean-
while 12,136 of GC-related targets were obtained from the
OMIM and GeneCards databases. The Venny 2.1.0 drawing
software was used to intersect the targets regulated by ost-
hole with the targets of GC, and 173 potential targets were
obtained, as shown in Figure 2(b).
3.2. Establishment and Analysis of Protein Interaction
Networks. The results show that the interaction network
consists of 173 nodes and 503 edges, as shown in Figure 3,
where each edge represents the interaction between each act-
ing target, and the higher the number of edges indicates the
more important the corresponding acting target of that
node. The top 10 targets of the screening results as the cen-
tral genes were as follows: MAPK3, MAPK1, SRC, AKT1,
HSP90AA1, RXRA, ESR1, RELA, MAPK8, and EGFR
(Figure 4).
3.3. GO and Pathway Analysis. As shown in Figure 5(a), the
top 10 metabolic process in the biological process categories
are indicators closely related to antitumor growth. In terms
of pathway analysis, 172 targets were involved in 10 KEGG
pathways, including apoptosis, PI3K/Akt, MAPK, IL-
17signaling pathway, and proteeoglycans in cancer with sig-
nificant P value of 0.01 (Figure 5(b)).
3.4. C-T-P-D Network Analysis. As shown in Figure 6, this
interaction network of compounds, targets, pathways, and
MAPK8
EGFR MAPK3
RELA MAPK1
32
36
36
35
RXRA HSP90AA1
SRC ESR1
AKT1
(b)
diseases has 185 nodes and 565 edges. The green nodes are
pathway disease cotargets, and the blue nodes are targets
that do not involve pathways. The red, purple, and orange
nodes represent diseases, pathways, and compounds, respec-
tively, and the edges represent their interactions.
3.5. Docking Result Analysis. Generally, the lower the energy
at which the ligand binds to the receptor in a stable confor-
mation, the greater the likelihood of an effect occurring.
Affinity is the score of molecular docking. The lower the
score, the stronger the binding affinity. In this study, the
binding energy ≤ −5 kJ/mol was used as the screening crite-
rion, and the compounds were molecularly docked with
the screened core targets. The results are shown in Table 1.
The results show that the binding energy of the com-
pound to the core target is less than −5 kJ/mol. These core
compounds and receptor proteins have low conformational
energy, stable structure, and high binding activity. Com-
pounds are better bound in the pocket cavity of the protein.
And it can form hydrogen bonds and hydrophobic interac-
tions with amino acid residues. The first four molecular
docking modes with better affinity are shown in Figure 7.
4. Discussion
In this study, a network pharmacology method was used to
screen out 173 common targets of osthole and GC and fur-
ther screen out the top ten core targets, including MAPK3,
MAPK1, SRC, AKT1, HSP90AA1, RXRA, ESR1, RELA,
MAPK14, and EGFR. According to the P value of each
enriched pathway and its relationship to GC, 173 targets
were involved in 10 pathways. Finally, a “C-T-P-D” network
based on osthole was constructed.
Among these core targets, the SRC family kinase (SFK)
represented by SRC is a class of nonreceptor tyrosine
kinases, and its role in signal transduction has been
Applied Bionics and Biomechanics 5

Bar chart of biological process categories Bar chart of cellular component categories Bar chart of molecular function categories
200 200 200

172

172

172
163
151
149

145
150 150 150

125
123
117

115
110

104
98
97
98

95
100 100 100

78
74
74

75
66
62

56
52
45

44
43
43
50 50 50

42

42

34
29
26
25
21
20
18

17
15
14
13

11
7
6
5

5
3

Microbody 3
Unclassified 2

3
3
Lipid droplet 1

1
1
1
0 0 0

Endoplasmic reticulum
All
Metabolic process
Biological regulation
Response to stimulus
Cell communication
Multicellular organismal process
Developmental process
Localization
Cellular component organization
Cell proliferation
Multi-organism process
Reproduction
Growth
Unclassified

All
Cytosol
Nucleus
Membrane-enclosed lumen
Membrane
Vesicle
Extracellular space
Endomembrane system
Mitochondrion
Cell projection
Cytoskeleton
Envelope
Chromosome
Golgi apparatus
Endosome
Vacuole

All
Protein binding
Ion binding
Nucleotide binding

Nucleic acid binding

Lipid binding
Chromatin binding

Oxygen binding
Carbohydrate binding
Unclassified
Protein-containing complex

Extracellular matrix

Transferase activity
Hydrolase activity
Molecular transducer activity
Enzyme regulator activity
Transporter activity
Antioxidant activity
Electron transfer activity
Translation regulator activity
Molecular adaptor activity
Structural molecule activity
(a)
Count
30.0
Apoptosis

PI3K-Akt signaling pathway 27.5

MAPK signaling pathway

Proteoglycans in cancer 25.0

FoxO signaling pathway

22.5
Relaxin signaling pathway

AGE-RAGE signaling pathway in cancer

20.0
TNF signaling pathway

L-17 signaling pathway

17.5

0.10 0.12 0.14 0.16

GeneRatio
0.10 0.14
0.12 0.16
(b)

Figure 5: (a) GO functional enrichment analysis of osthole in gastric cancer. (b) KEGG pathway enrichment analysis of osthole in gastric
cancer.

extensively studied [15]. Current studies have found that
SRC is abnormally expressed or increased in activity in gas-
tric cancer tissue and is involved in the occurrence and
development of gastric cancer. It was reported for the first
time that the exosome derived from gastric cancer cell
SGC7901 has continuous activation of Src kinase in the pro-
cess of promoting gastric cancer cell proliferation [16]. It is
suggested that SRC kinase may play a promoting role in
the malignant proliferation and metastasis of gastric cancer
cells. In addition, the growth and metastasis of gastric cancer
depend on angiogenesis. VEGF is the most powerful cyto-
kine known to promote vascular endothelial growth and is
a relatively independent factor in determining the poor
prognosis of gastric cancer patients [17], and the activation
of SRC can upregulate VEGF expression, which also proved
the role of SRC in gastric cancer. Akt-1, also known as pro-
tein kinase B, can form biologically active phosphorylated
Akt-1 (pAkt-1) after being stimulated by upstream signals.
Katrina et al. studied 50 cases of advanced gastric cancer
and found that the positive rate of pAkt-1 was 68%, and it
was significantly related to the depth of tumor invasion
and lymph node metastasis [18]. At the same time, several
6 Applied Bionics and Biomechanics

Figure 6: The Compound–Target–Pathway–Disease network (the green nodes are pathway disease cotargets; the blue nodes are targets that
do not involve pathways. The red, purple, and orange nodes represent diseases, pathways, and compounds; edges represent their
interactions).

Table 1: Binding energy values of core compounds of osthole and bition of EGFR expression can induce tumor cell death
core targets. [21]. In summary, it can be seen that the core targets are
closely related to the occurrence and development of GC.
Proteins PDB ID Binding energy/(kcal/Mol) As shown in the bubble chart, the PI3K/AKT signaling
AKT1 2uzs -6.0 pathway and the MAPK signaling pathway accounted for a
EGFR 1m17 -7.3 large number of targets. Phosphatidylinositol 3-kinase
ESR1 1err -6.0
(PI3K) is an intracellular phosphatidylinositol kinase that
upon activation produces the second messenger PIP3 at
HSP90AA1 1qz2 -6.1
the plasma membrane and intracellular AKT. After binding
MAPK1 1pme -7.9 to PIP3, it is transferred from the cytoplasm to the inside of
MAPK3 2zoq -8.1 the cell membrane for phosphorylation. As a key node in the
MAPK14 1a9u -6.3 pathway, AKT can affect the activation state of various
RELA 1nfi -6.2 downstream effector molecules. Studies have shown that in
SRC 1a07 -8.0 gastric cancer, osthole induces G2/M arrest and apoptosis
RXRA 1dsz -6.1 by regulating the PI3K/Akt pathway. Osthole also exhibits
proapoptotic properties in nude mouse retinoblastoma by
inhibiting PI3K/Akt/mTOR signaling pathway activation
[22, 23]. At the same time, PI3K/AKT pathway inhibitors
studies [19, 20] have shown that the expression of pAkt-1 combined with chemotherapy can attenuate the chemoresis-
leads to resistance to chemotherapy and radiotherapy. The tance of GC cell lines [24]. MAPK signaling pathway is the
EGFR gene is overexpressed in gastric cancer and is associ- downstream signal of multiple pathways, involved in multi-
ated with prognosis. Studies have shown that targeted inhi- ple proliferation, differentiation and survival pathways.
Applied Bionics and Biomechanics
Osthole-MAPK3
Osthole-MAPK1
Figure 7: Three-dimensional graphs showing the binding of osthole and core target (binding energy ≤ −7 kJ/mol).
Meanwhile, MAPK1 and MAPK3 are also key sites of
MAPK signaling pathway. In conclusion, we speculate that
osthole can target MAPK3, MAPK1, AKT1, and other cen-
tral targets to regulate PI3K/AKT signaling pathway, MAPK
signaling pathway, and various signaling pathways. This
may be the main mechanism of osthole against gastric
cancer.
Molecular docking results showed that the binding ener-
gies of osthole and core targets were all less than −5 kJ/mol,
which indicated that these core compounds had higher
binding activities to receptor proteins, which further verified
the results obtained by network pharmacology.
In summary, this study used network pharmacology and
molecular docking technology to preliminarily explore the
multiple targets, biological functions, signaling pathways,
and possible mechanisms of osthole in the treatment of gas-
tric cancer and molecular docking to verify the results. The
results show that osthole may act on MAPK3, MAPK1,
AKT1, SRC, and other targets through PI3K/AKT, MAPK,
and other signaling pathways, indicating that osthole has
the potential to synergistically treat gastric cancer through
multiple components, multiple targets, and multiple path-
ways. This study is mainly based on a web-based pharmacol-
ogy and bioinformatics database. Therefore, there are some
limitations. In the following studies, these data need to be
further experimentally verified at the cellular, animal, and
molecular levels to provide an experimental basis for the
treatment of GC with osthole. It is hoped that osthole can
become a new potential anti-GC drug.
7
Osthole-EGFR
Othhole-SRC
Data Availability
The data used to support the findings of this study are avail-
able from the corresponding author upon request.
Conflicts of Interest
The author declared that there are no conflicts of interest to
this work.
Acknowledgments
The author thanks Bao Haiyan for optimizing the figure.
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