Mechanism of Cnidii Fructus in the treatment of periodontitis with osteoporosis based on network pharmacology, molecular docking, and molecular dynamics simulation

doi:10.7518/hxkq.2025.2024275

Abstract

Abstract:

Objective This study aimed to explore the active components, potential targets, and mechanism of Cnidii Fructus in the treatment of periodontitis with osteoprosis through network pharmacology, molecular docking, and molecular dynamics simulation technology. Methods The main chemical constituents and targets of Cnidii Fructus were screened using the TCMSP and SwissTargetPrediction databases, as well as literature reports. Targets of periodontitis and osteoporosis were predicted using different databases. The intersection targets of Cnidii Fructus, periodontitis, and osteoporosis were obtained using Venny 2.1. The protein-protein interaction network was formed on the STRING platform. Cytoscape 3.9.1 was used to construct the active component-intersection target interaction network, perform the topological analysis, and screen key targets and core active components. Furthermore, the Metascape database was used to perform gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis on the intersection targets. The top five key targets and core active components were selected as receptor proteins and ligand small molecules. Discovery Studio 2019 was used to dock ligands and receptors and visualize the docking results. Molecular dynamics simulation was conducted using Gromacs2022.3 to assess the stability of the interactions between the core active components and the main targets. Results A total of 20 potential active ingredients of Cnidii Fructus were screened, and 116 targets of Cnidii Fructus were obtained for treating periodontitis and osteoporosis. GO and KEGG analysis of the 116 targets showed that Cnidii Fructus may play a therapeutic role through the phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) and advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) signaling pathways. Molecular docking showed that the core constituents were well bound to the main targets. Molecular dynamics simulations confirmed the stability of the Diosmetin-AKT1 complex system. Conclusion The preliminary discovery of the potential molecular pharmacological mechanism of Cnidii Fructus extract in the targeted treatment of periodontitis with osteoporosis through a multi-component, multitarget, and multi-pathway approach can serve as a theoretical foundation for future drug-development research and clinical application.

Key words: Cnidii Fructus, periodontitis, osteoporosis, network pharmacology, molecular docking, molecular dynamics simulation

CLC Number:

R781.4

Feng Miaomiao, Xu Xiaoran, Li Ningli, Yang Mingzhen, Zhai Yuankun. Mechanism of Cnidii Fructus in the treatment of periodontitis with osteoporosis based on network pharmacology, molecular docking, and molecular dynamics simulation[J]. West China Journal of Stomatology, 2025, 43(2): 249-261.

Figures/Tables 11

Tab 1

Fig 1

Fig 2

Fig 3

Fig 4

Fig 5

Fig 6

Tab 2

Fig 7

Fig 8

Fig 9

References 52

1	Cui Y, Hong S, Xia Y, et al. Melatonin engineering M2 macrophage-derived exosomes mediate endoplasmic reticulum stress and immune reprogramming for periodontitis therapy[J]. Adv Sci (Weinh), 2023, 10(27): e230-2029.
2	赖静, 余昕, 郭姗姗. 牙周炎和骨质疏松症相关性研究现状的探讨[J]. 现代医学与健康研究, 2023, 7(15): 131-134.
	Lai J, Yu X, Guo SS. Discussion on the current research status of the correlation between periodontitis and osteoporosis[J]. Modern Med Health Res, 2023, 7(15): 131-134.
3	Yu B, Wang CY. Osteoporosis and periodontal disea-ses—An update on their association and mechanistic links[J]. Periodontol 2000, 2022, 89(1): 99-113.
4	刘小雨, 郭瑞生, 吕方启. 慢性牙周炎与骨质疏松症相关性的研究进展[J]. 中国药物经济学, 2022, 17(11): 125-128.
	Liu XY, Guo RS, Lü FQ. Research progress on the relationship between chronic periodontitis and osteoporosis[J]. China J Pharma Econ, 2022, 17(11): 125-128.
5	郑学彬. 补肾固齿丸佐治慢性牙周炎合并骨质疏松对骨代谢和牙槽骨改变的影响[J]. 中国药业, 2018, 27(15): 37-40.
	Zheng XB. Clinical effect of Bushen Guchi Pills in the adjuvant treatment of chronic periodontitis complicated with osteoporosis and its effect on the changes of bone metabolism and alveolar bone[J]. China Pharma, 2018, 27(15): 37-40.
6	Li N, Xie L, Wu Y, et al. Dexamethasone-loaded zeolitic imidazolate frameworks nanocomposite hydrogel with antibacterial and anti-inflammatory effects for periodontitis treatment[J]. Mater Today Bio, 2022, 16: 100360.
7	Xu S, Hu B, Dong T, et al. Alleviate periodontitis and its comorbidity hypertension using a nanoparticle-embedded functional hydrogel system[J]. Adv Healthc Mater, 2023, 12(20): e2203337.
8	Contaldo M, D’Ambrosio F, Ferraro GA, et al. Antibiotics in dentistry: a narrative review of the evidence beyond the myth[J]. Int J Environ Res Public Health, 2023, 20(11): 6025.
9	孟焕新. 牙周病学[M]. 5版. 北京: 人民卫生出版社, 2020: 227-230.
	Meng HX. Periodontology[M]. 5th ed. Beijing: People’s Medical Publishing House, 2020: 227-230.
10	Gao F, Hu Y, Ye X, et al. Optimal extraction and fingerprint analysis of Cnidii fructus by accelerated solvent extraction and high performance liquid chromatographic analysis with photodiode array and mass spectrometry detections[J]. Food Chem, 2013, 141(3): 1962-1971.
11	郑苏阳, 马勇, 郭杨, 等. “温肾通络止痛方” 治疗原发性骨质疏松症的疗效观察及处方优化[J]. 辽宁中医杂志, 2016, 43(10): 2098-2100.
	Zheng SY, Ma Y, Guo Y, et al. Treating primary osteoporosis with prescription of Warming Kidney and Remo-ving Obstruction in Channels to Relieve Pain and formula optimization[J]. Liaoning J Tradit Chin Med, 2016, 43(10): 2098-2100.
12	陈亚琼, 高鹏, 沈慧. 蛇床子素通过调控miR-26a表达对人牙周膜干细胞生物学特性的影响[J]. 中成药, 2023, 45(5): 1690-1693.
	Chen YQ, Gao P, Shen H. Effects of osthole on the biological properties of human periodontal ligament stem cells by regulating the expression of miR-26a[J]. Chin Tradit Pat Med, 2023, 45(5): 1690-1693.
13	袁文秀, 王旭霞, 张丽娜, 等. 蛇床子素对大鼠正畸牙牙周组织改建的影响[J]. 上海口腔医学, 2019, 28(6): 561-566.
	Yuan WX, Wang XX, Zhang LN, et al. Effect of osthole on periodontal remodeling during orthodontic tooth mo-vement in rats[J]. Shanghai J Stomatol, 2019, 28(6): 561-566.
14	Hopkins AL. Network pharmacology[J]. Nat Biotechnol, 2007, 25(10): 1110-1111.
15	Wang CR, Chen HW, Li Y, et al. Network pharmacology exploration reveals anti-apoptosis as a common therapeutic mechanism for non-alcoholic fatty liver disease treated with blueberry leaf polyphenols[J]. Nutrients, 2021, 13(11): 4060.
16	Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules[J]. Nucleic Acids Res, 2019, 47(W1): W357-W364.
17	Consortium UniProt. UniProt: a worldwide hub of protein knowledge[J]. Nucleic Acids Res, 2019, 47(D1): D506-D515.
18	Pan S, Hu B, Sun J, et al. Identification of cross-talk pathways and ferroptosis-related genes in periodontitis and type 2 diabetes mellitus by bioinformatics analysis and experimental validation[J]. Front Immunol, 2022, 13: 1015491.
19	Han J, Wang Y, Zhou H, et al. CD137 regulates bone loss via the p53 wnt/β-catenin signaling pathways in aged mice[J]. Front Endocrinol (Lausanne), 2022, 13: 922501.
20	Szklarczyk D, Gable AL, Lyon D, et al. STRING v11: protein-protein association networks with increased co-verage, supporting functional discovery in genome-wide experimental datasets[J]. Nucleic Acids Res, 2019, 47(D1): D607-D613.
21	Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets[J]. Nat Commun, 2019, 10(1): 1523.
22	Gene Ontology Consortium. The Gene Ontology resour-ce: enriching a GOld mine[J]. Nucleic Acids Res, 2021, 49(D1): D325-D334.
23	袁炜, 耿辉, 王馨笛, 等. 生物信息综合数据库KEGG的应用[J]. 中国循证心血管医学杂志, 2022, 14(6): 669-673.
	Yuan W, Geng H, Wang XD, et al. Application of database of Kyoto encyclopedia of genes and genomes, a comprehensive bioinformatics database[J]. Chin J Evid-Based Cardiovasc Med, 2022, 14(6): 669-673.
24	Wang L, Wang Y, Yang W, et al. Network pharmacology and molecular docking analysis on mechanisms of Tibetan Hongjingtian (Rhodiola crenulata) in the treatment of COVID-19[J]. J Med Microbiol, 2021, 70(7): 001374.
25	Kim S, Chen J, Cheng T, et al. PubChem in 2021: new data content and improved web interfaces[J]. Nucleic Acids Res, 2021, 49(D1): D1388-D1395.
26	Yin B, Bi YM, Fan GJ, et al. Molecular mechanism of the effect of Huanglian Jiedu decoction on type 2 diabetes mellitus based on network pharmacology and molecular docking[J]. J Diabetes Res, 2020, 2020: 5273914.
27	Burley SK, Bhikadiya C, Bi C, et al. RCSB Protein Data Bank (RCSB.org): delivery of experimentally-determined PDB structures alongside one million computed structure models of proteins from artificial intelligence/machine learning[J]. Nucleic Acids Res, 2023, 51(D1): D488-D508.
28	Wang S, Li Y, Wang J, et al. ADMET evaluation in drug discovery. 12. Development of binary classification models for prediction of hERG potassium channel blockage[J]. Mol Pharm, 2012, 9(4): 996-1010.
29	Cheng T, Li X, Li Y, et al. Comparative assessment of scoring functions on a diverse test set[J]. J Chem Inf Mo-del, 2009, 49(4): 1079-1093.
30	Rampogu S, Park C, Ravinder D, et al. Pharmacotherapeutics and molecular mechanism of phytochemicals in alleviating hormone-responsive breast cancer[J]. Oxid Med Cell Longev, 2019, 2019: 5189490.
31	Pronk S, Páll S, Schulz R, et al. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit[J]. Bioinformatics, 2013, 29(7): 845-854.
32	Elekofehinti OO, Iwaloye O, Josiah SS, et al. Molecular docking studies, molecular dynamics and ADME/tox reveal therapeutic potentials of STOCK1N-69160 against papain-like protease of SARS-CoV-2[J]. Mol Divers, 2021, 25(3): 1761-1773.
33	祁巧玲, 王梦婷, 陈蕊, 等. 治疗牙周炎所致牙槽骨吸收的前景药物[J]. 中国医院药学杂志, 2016, 36(3): 244-249.
	Qi QL, Wang MT, Chen R, et al. Prospective drugs in the treatment of alveolar bone loss in periodontitis[J]. Chin J Hosp Pharm, 2016, 36(3): 244-249.
34	Sanz M, Beighton D, Curtis MA, et al. Role of microbial biofilms in the maintenance of oral health and in the development of dental caries and periodontal diseases. Consensus report of group 1 of the Joint EFP/ORCA workshop on the boundaries between caries and perio-dontal disease[J]. J Clin Periodontol, 2017, 44 : S5-S11.
35	杨卫, 赵品, 陶美玲, 等. 淫羊藿苷口服给药对骨质疏松牙周炎小鼠牙槽骨吸收的影响[J]. 上海口腔医学, 2019, 28(1): 30-35.
	Yang W, Zhao P, Tao ML, et al. Effect of oral administration of icariin on periodontitis associated alveolar bone resorption in an osteoporosis mouse model[J]. Shanghai J Stomatol, 2019, 28(1): 30-35.
36	Khan SA, Wu Y, Li AS, et al. Network pharmacology and molecular docking-based prediction of active compounds and mechanisms of action of Cnidii Fructus in treating atopic dermatitis[J]. BMC Complement Med Ther, 2022, 22(1): 275.
37	Xiong Y, Zhao B, Zhang W, et al. Curcumin promotes osteogenic differentiation of periodontal ligament stem cells through the PI3K/AKT/Nrf2 signaling pathway[J]. Iran J Basic Med Sci, 2020, 23(7): 954-960.
38	Mukherjee A, Rotwein P. Selective signaling by Akt1 controls osteoblast differentiation and osteoblast-media-ted osteoclast development[J]. Mol Cell Biol, 2012, 32(2): 490-500.
39	Gui X, Chen H, Cai H, et al. Leptin promotes pulmonary fibrosis development by inhibiting autophagy via PI3K/Akt/mTOR pathway[J]. Biochem Biophys Res Commun, 2018, 498(3): 660-666.
40	姬晓炜, 冯凯, 吴泽钰, 等. 基于网络药理学和分子对接探讨香加皮防治牙周炎的作用机制[J]. 新疆医科大学学报, 2022, 45(8): 867-879.
	Ji XW, Feng K, Wu ZY, et al. To explore mechanism of Cortex Periplocae Radicis in prevention and treatment of periodontitis based on network pharmacology and molecular docking[J]. J Xinjiang Med Univ, 2022, 45(8): 867-879.
41	Yang X, Jiang T, Wang Y, et al. The role and mechanism of SIRT1 in resveratrol-regulated osteoblast autophagy in osteoporosis rats[J]. Sci Rep, 2019, 9(1): 18424.
42	Liu F, Huang X, He JJ, et al. Plantamajoside attenuates inflammatory response in LPS-stimulated human gingival fibroblasts by inhibiting PI3K/AKT signaling pathway[J]. Microb Pathog, 2019, 127: 208-211.
43	Pan JM, Wu LG, Cai JW, et al. Dexamethasone suppres-ses osteogenesis of osteoblast via the PI3K/Akt signa-ling pathway in vitro and in vivo [J]. J Recept Signal Transduct Res, 2019, 39(1): 80-86.
44	Li M, Pan Z, He Q, et al. Arctiin attenuates iron over-load‑induced osteoporosis by regulating the PI3K/Akt pathway[J]. Int J Mol Med, 2023, 52(5): 108.
45	Goldin A, Beckman JA, Schmidt AM, et al. Advanced glycation end products: sparking the development of diabetic vascular injury[J]. Circulation, 2006, 114(6): 597-605.
46	Nonaka K, Kajiura Y, Bando M, et al. Advanced glycation end-products increase IL-6 and ICAM-1 expression via RAGE, MAPK and NF-κB pathways in human gingival fibroblasts[J]. J Periodontal Res, 2018, 53(3): 334-344.
47	Abbass MM, Korany NS, Salama AH, et al. The relationship between receptor for advanced glycation end products expression and the severity of periodontal disease in the gingiva of diabetic and non diabetic periodontitis patients[J]. Arch Oral Biol, 2012, 57(10): 1342-1354.
48	Shen CY, Lu CH, Wu CH, et al. The development of maillard reaction, and advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling inhibitors as novel therapeutic strategies for patients with AGE-related diseases[J]. Molecules, 2020, 25(23): 5591.
49	Asadipooya K, Uy EM. Advanced glycation end pro-ducts (AGEs), receptor for AGEs, diabetes, and bone: review of the literature[J]. J Endocr Soc, 2019, 3(10): 1799-1818.
50	Zhu C, Shen S, Zhang S, et al. Autophagy in bone remodeling: a regulator of oxidative stress[J]. Front Endocrinol (Lausanne), 2022, 13: 898634.
51	马遥, 姜兆伟, 靳云轶, 等. 大鼠牙周炎正畸牙移动初期TNF信号通路的基因本体分析[J].口腔疾病防治, 2019, 27(11): 695-702.
	Ma Y, Jiang ZW, Jin YY, et al. Gene ontology analysis of the TNF signaling pathway in early orthodontic tooth movement of rats with periodontitis[J]. J Prev Treat Stomatol Dis, 2019, 27(11): 695-702.
52	Wang X, Pei Z, Hao T, et al. Prognostic analysis and validation of diagnostic marker genes in patients with osteoporosis[J]. Front Immunol, 2022, 13: 987937.

编号	Mol ID	活性成分	OB/%	DL
1	MOL001510	24-epicampesterol	37.58	0.71
2	MOL001771	poriferast-5-en-3beta-ol	36.91	0.75
3	MOL001941	Ammidin	34.55	0.22
4	MOL002881	Diosmetin	31.14	0.27
5	MOL002883	Ethyl oleate （NF）	32.40	0.19
6	MOL000358	beta-sitosterol	36.91	0.75
7	MOL003584	Xanthoxylin N	35.51	0.21
8	MOL003588	Prangenidin	36.31	0.22
9	MOL003591	ar-curcumene	52.34	0.65
10	MOL003600	cnidimol B	68.66	0.26
11	MOL003604	cnidimol F	54.43	0.28
12	MOL003605	（E）-2,3-bis （2-keto-7-methoxy-chromen-8-yl） acrolein	56.38	0.71
13	MOL003606	cniforin A	55.89	0.47
14	MOL003607	cniforin B	36.70	0.60
15	MOL003608	O-Acetylcolumbianetin	60.04	0.26
16	MOL003617	isogosferol	30.07	0.25
17	MOL003624	O-Isovalerylcolum bianetin	64.03	0.36
18	MOL003626	Ostruthin	30.65	0.23
19	MOL000449	Stigmasterol	43.83	0.76
20	MOL000614	osthol	38.75	0.13

靶点	PDB ID	-CIE
靶点	PDB ID	美花椒内酯	蛇床子素	香叶木素	(E)-2,3-bis (2-keto-7-methoxy-chromen-8-yl) acrolein	O-乙酰二氢欧山芹酯
BCL2	4lxd	22.60	26.47	26.39	NA	31.16
CASP3	1rhm	27.27	26.32	34.22	43.43	31.47
JUN	4y46	30.18	33.07	34.59	42.93	35.47
AKT1	4ejn	31.79	38.05	44.33	56.19	40.55
PPARG	6t1s	32.02	34.55	40.70	47.64	36.71

[1]	Zhang Xueying, Meng Xin, Liu Zhizhen, Zhang Kang, Ji Honghai, Sun Minmin. Ginsenoside Rb3 regulates the phosphorrylated extracellular signal-regulated kinase signaling pathway to alleviate inflammatory responses and promote osteogenesis in rats with periodontitis [J]. West China Journal of Stomatology, 2025, 43(2): 236-248.
[2]	Fu Lanqing, Hao Xinyu, Qian Wenbo, Sun Ying. Effects of initial periodontal therapy on the formation of neutrophil extracellular traps in gingival crevicular fluid in patients with severe periodontitis [J]. West China Journal of Stomatology, 2025, 43(1): 46-52.
[3]	Chen Yuxiang, Zhao Anna, Yang Haoran, Yang Xia, Cheng Tingting, Rao Xianqi, Li Ziliang. Role of fatty acid metabolism-related genes in periodontitis based on machine learning and bioinformatics analysis [J]. West China Journal of Stomatology, 2024, 42(6): 735-747.
[4]	Shi Yuan, Su Jimei, Lü Lihua, Wu Dingwen. A case of hypophosphatemia rickets with unidentified apical periodontitis as the initial symptom of diagnosis [J]. West China Journal of Stomatology, 2024, 42(6): 832-838.
[5]	Zhou Lulu, Teng Nian, Gao Tiantian, Wang Hongbin, Gao Xiang. Protective effect of carvacrol hydrogel on the alveolar bone in rats with periodontitis [J]. West China Journal of Stomatology, 2024, 42(5): 593-608.
[6]	Song Ziyi, Yang Chao, Zhang Yunlong, Zhang Zhujiang, Ren Tianjiao, Zhang Xinyue, Li Xue. Mechanism of mangiferin in the treatment of oral submucous fibrosis based on Gene Expression Omnibus database chip mining combined with network pharmacology and molecular docking [J]. West China Journal of Stomatology, 2024, 42(4): 444-451.
[7]	Li Qiong, Ma Haonan, Shang Yaqi, Xin Xirui, Liu Xinchan, Wu Zhou, Yu Weixian. The role of uncoupling protein 2 in experimental periodontitis-associated renal injury in rats [J]. West China Journal of Stomatology, 2024, 42(4): 502-511.
[8]	Yang Rongxia, Zong Yingrui, Zhang Chen. Potential correlation between chronic periodontitis and Parkinson’s disease [J]. West China Journal of Stomatology, 2024, 42(4): 521-530.
[9]	Li Yue, Xu Chunmei, Xie Xudong, Shi Peilei, Wang Jun, Ding Yi. Temporal and spatial expression analysis of periostin in mice periodontitis model [J]. West China Journal of Stomatology, 2024, 42(3): 286-295.
[10]	Xin Yu, Fu Ruobing, Xin Xirui, Shang Yaqi, Liu Xinchan, Yu Weixian. Role of connexin 43 in a rat model of periodontitis-induced renal injury [J]. West China Journal of Stomatology, 2024, 42(3): 296-303.
[11]	Chen Hong, Zhang Ronghua, Zhao Yuan. Non-surgical treatment of maxillary lateral incisor double dens invaginatus type Ⅲ with apical periodontitis [J]. West China Journal of Stomatology, 2024, 42(3): 409-414.
[12]	Ma Haonan, Li Qiong, Shang Yaqi, Xin Xirui, Liu Xinchan, Wu Zhou, Yu Weixian. Impact of circadian clock protein Bmal1 on experimentally-induced periodontitis-associated renal injury [J]. West China Journal of Stomatology, 2024, 42(2): 163-171.
[13]	Sun Jinmeng, Zhang Ying, Zheng Zejun, Ding Xiaoling, Sun Minmin, Ding Gang. Potential mechanism of ginseng in the treatment of periodontitis based on network pharmacology and molecular docking [J]. West China Journal of Stomatology, 2024, 42(2): 181-191.
[14]	Ye Changchang, Yang He, Huang Ping. Application of intentional replantation in advanced periodontitis involving teeth preservation [J]. West China Journal of Stomatology, 2024, 42(1): 12-18.
[15]	Wang Jun.. Vital pulp therapy of permanent teeth with irreversible pulpitis [J]. West China Journal of Stomatology, 2023, 41(6): 622-627.