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J Zhejiang Univ (Med Sci)  2022, Vol. 51 Issue (1): 62-72    DOI: 10.3724/zdxbyxb-2021-0230
    
Molecular mechanism of ovarian toxicity of Tripterygium wilfordii Hook.F.: a study based on network pharmacology and molecular docking
WANG Zhiqiang1,2,GONG Caixia3,LI Zhenbin1,2,*()
1. Department of Rheumatology and Clinical Immunology, the 980th Hospital of the Joint Logistic Support Force of the People’s Liberation Army, Shijiazhuang 050082, China;
2. First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China;
3. Department of Nephrology, Shijiazhuang Ping’an Hospital, Shijiazhuang 050012, China
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Abstract  

Objective: To explore the mechanism of ovarian toxicity of Tripterygium wilfordii Hook. F. (TwHF) by network pharmacology and molecular docking. Methods: The candidate toxic compounds and targets of TwHF were collected by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the Comparative Toxicogenomics Database (CTD). Then, the potential ovarian toxic targets were obtained from CTD, and the target genes of ovarian toxicity of TwHF were analyzed using the STRING database. The protein-protein interaction (PPI) network was established by Cytoscape and analyzed by the cytoHubba plug-in to identify hub genes. Additionally, the target genes of ovarian toxicity of TwHF were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses by using the R software. Finally, Discovery Studio software was used for molecular docking verification of the core toxic compounds and the hub genes. Results: Nine candidate toxic compounds of TwHF and 56 potential ovarian toxic targets were identified in this study. Further network analysis showed that the core ovarian toxic compounds of TwHF were triptolide, kaempferol and tripterine, and the hub ovarian toxic genes included TP53, MYC, PTEN, MAPK3, MTOR, STAT3, EGFR, KRAS, CDH1 and AKT1. Besides, the GO and KEGG analysis indicated that TwHF caused ovarian toxicity through oxidative stress, reproductive system development and function, regulation of cell cycle, response to endogenous hormones and exogenous stimuli, apoptosis regulation and aging. The docking studies suggested that 3 core ovarian toxic compounds of TwHF were able to fit in the binding pocket of the 10 hub genes. Conclusion: TwHF may cause ovarian toxicity by acting on 10 hub genes and 140 signaling pathways.



Key wordsTripterygium wilfordii Hook.F.      Ovarian toxicity      Network pharmacology      Target      Pathway     
Received: 08 August 2021      Published: 17 May 2022
CLC:  R285.5  
Corresponding Authors: LI Zhenbin     E-mail: lizb1962@126.com
Cite this article:

WANG Zhiqiang,GONG Caixia,LI Zhenbin. Molecular mechanism of ovarian toxicity of Tripterygium wilfordii Hook.F.: a study based on network pharmacology and molecular docking. J Zhejiang Univ (Med Sci), 2022, 51(1): 62-72.

URL:

https://www.zjujournals.com/med/10.3724/zdxbyxb-2021-0230     OR     https://www.zjujournals.com/med/Y2022/V51/I1/62


基于网络药理学和分子对接技术探讨雷公藤卵巢毒性的机制

目的:通过网络药理学和分子对接技术探讨雷公藤卵巢毒性的作用机制。方法:通过中药系统药理数据库及分析平台(TCMSP)和比较毒理基因组学数据库(CTD)收集雷公藤的候选毒性化合物和靶点,从CTD中获得雷公藤潜在的卵巢毒性靶点,并利用STRING数据库对雷公藤卵巢毒性的靶点基因进行分析。用Cytoscape软件构建蛋白质-蛋白质相互作用(PPI)网络,用cytoHubba插件鉴定核心基因。此外,利用R软件对雷公藤卵巢毒性的靶点基因进行基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析。最后,使用Discovery Studio软件对核心毒性化合物和核心基因进行分子对接验证。结果:共获得9个雷公藤候选毒性化合物和56个潜在的卵巢毒性靶点。网络分析结果,雷公藤甲素、山柰酚和雷公藤红素是雷公藤的关键卵巢毒性化合物,核心卵巢毒性基因包括TP53MYCPTENMAPK3MTORSTAT3EGFRKRASCDH1AKT1。GO和KEGG分析显示,雷公藤通过氧化应激、生殖系统发育和功能、细胞周期调节、对内源性激素和外源性刺激的反应、细胞凋亡调节、衰老等途径引起卵巢毒性。分子对接研究显示,雷公藤的3个关键卵巢毒性化合物可与10个核心基因的对接口袋相匹配。结论:雷公藤可能通过作用于10个核心基因和140条信号通路而导致卵巢毒性。


关键词: 雷公藤,  卵巢毒性,  网络药理学,  靶点,  通路 

化合物

化学结构式

CAS编号

相对分子质量

口服生物利用度(%)

类药性

靶点数

β-谷甾醇(β-sitosterol)

83-46-5

414.79

36.91

0.75

20

山柰酚(kaempferol)

520-18-3

286.25

41.88

0.24

174

豆甾醇(stigmasterol)

83-48-7

412.77

43.83

0.76

42

雷公藤红素(tripterine 或celastrol)

34157-83-0

450.67

17.84

0.78

162

雷公藤甲素(triptolide)

38748-32-2

360.44

51.29

0.68

575

雷公藤氯内酯醇(tripchlorolide)

132368-08-2

396.90

78.72

0.72

7

异黄腐醇(isoxanthohumol)

521-48-2

354.43

56.81

0.39

3

雷公藤内酯酮(triptonide)

38647-11-9

358.42

68.45

0.68

10

川陈皮素(nobiletin)

478-01-3

402.43

61.67

0.52

34

Table 1 The candidate toxic compounds and the corresponding targets of Hook.F.
Figure 1 The toxic compound-ovarian toxic target network of Hook.F.
Figure 2 Protein-protein interaction network of ovarian toxicity targets of Hook.F.

基因名称

蛋白质名称

UniProt ID

度值

最大团中心性

生物体

TP53

P53蛋白

P04637

41

648364160437

智人

MYC

MYC蛋白

P01106

35

648364038744

智人

PTEN

PTEN蛋白

P60484

32

648363225024

智人

MAPK3

促分裂原活化的蛋白激酶3

P27361

34

648352501921

智人

MTOR

哺乳动物雷帕霉素靶蛋白

P42345

29

648351612720

智人

STAT3

信号转导及转录激活因子3

P40763

29

648336689282

智人

EGFR

表皮生长因子受体

P00533

31

648268145402

智人

KRAS

KRAS蛋白

P01116

29

648267096960

智人

CDH1

钙黏着蛋白1

P12830

25

647689997646

智人

AKT1

Akt激酶1

P31749

34

642097136160

智人

Table 2 Details of the hub genes in protein-protein interaction networks of ovarian toxicity targets of Hook.F.
Figure 3 The top 20 of Gene Ontology(GO) enrichment analysis of ovarian toxicity targets of Hook.F.
Figure 4 The top 20 of KEGG enrichment analysis of ovarian toxicity targets of Hook.F.
Figure 5 Molecular docking pattern diagram of triptolide with hub genes of ovarian toxicity

毒性靶点基因

PDB ID

RMSD (×10–10 m)

CDOCKER相互作用能 (kJ/mol)

雷公藤甲素

山柰酚

雷公藤红素

原配体

TP53

5HMH

0.474937

137.2

267.1

298.6

309.1

MYC

6U80

0.280991

157.4

228.3

263.3

184.0

PTEN

4C4F

0.213419

134.5

236.2

212.9

170.7

MAPK3

4QTB

1.212460

182.1

283.5

193.3

360.9

MTOR

4HVB

0.753273

166.4

302.6

263.9

245.6

STAT3

5E1E

0.754705

204.2

205.9

194.7

216.0

EGFR

5D41

0.458168

94.1

239.0

183.8

223.4

KRAS

6GJ5

0.646935

145.8

144.5

164.9

156.4

CDH1

3FF8

125.8

239.3

197.3

AKT1

3OS5

0.945302

172.6

191.1

183.9

207.6

Table 3 The CDOCKER interaction energy between core toxic compounds and hub ovarian toxicity target genes of Hook.F.in molecular docking
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