Mechanistic investigation of Kuntai capsule in endometriosis treatment: A network pharmacology, molecular docking, and molecular dynamics simulation approach

Abstract

Objective: To explore the mechanism of action of Kuntai capsule in the treatment of endometriosis (EMT).

Methods: The active components and corresponding targets of Kuntai capsule were obtained from the TCMSP, BATMAN-TCM, Pubchem, and SwissTargetPrediction databases. EMT-related disease targets were retrieved from GeneCards, DisGeNET, TTD, OMIM, and Drugbank. A Venn diagram was employed to identify the intersection targets of Kuntai capsule and EMT. The disease-component-target network was constructed using Cytoscape, and the common target protein-protein interaction (PPI) network was built using the STRING database. Topological analysis of the PPI network was performed using Cytoscape to screen for core targets. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the DAVID database. Molecular docking was performed with AutoDockTools. The stability of the optimal binding energy model was further validated using GROMACS molecular dynamics simulations.

Results: A total of 182 common targets were identified. The core components included sitosterol, panicolin, and rivularin. Among them, TNF, GAPDH, and AKT1 were found to play significant roles in the biological network of Kuntai capsule in treating EMT. These core targets are primarily involved in processes such as the negative regulation of apoptosis pathway and oncogenic pathway such as the PI3K-Akt signaling, which plays a therapeutic role in EMT. Molecular docking and molecular dynamics simulations further confirmed the stable and tight binding of sitosterol to AKT1.

Conclusion: Kuntai capsule may exert therapeutic effects in EMT by activating multiple signaling pathways through the regulation of core targets such as TNF. These findings not only enhance our understanding of the mechanism of action of Kuntai capsule but also provides new insights into the potential clinical applications of traditional Chinese medicine (TCM) in EMT treatment. Future research can further explore how TCM drugs can intervene in the pathological processes of EMT.

Keywords

Kuntai capsule / Endometriosis / Network pharmacology / Molecular docking / Molecular dynamics simulation

Declarations

Not applicable.

Authors' contributions

Shanshan Li: Conceptualization, Methodology, Software, Data curation, Writing - Original draft preparation, Writing - Reviewing and Editing. Longhui Shen: Visualization, Investigation, Supervision, Validation.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This study was supported by Ningbo Clinical Research Center for Gynaecological Diseases (2024L002) and Zhejiang Pharmaceutical Association Special Project on Rational Drug Use in Primary Hospitals (2025JCYY04).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

Not applicable.

Authors' other information

Not applicable.

References

[1] Doroftei B, Ilie OD, Balmus IM, et al. Molecular and clinical insights on the complex interaction between oxidative stress, apoptosis, and endobiota in the pathogenesis of endometriosis. Diagn (Basel). 2021; 11(8):1434. https://doi.org/10.3390/diagnostics11081434

[2] Chinese Physicians Association of Obstetricians and Gynecologists, Chinese Medical Association of Obstetrics and Gynecology, Endometriosis Collaborative Group. Guidelines for the diagnosis and treatment of endometriosis (third edition)[J]. Chinese Journal of Obstetrics and Gynecology, 2021, 56(12): 812-824. https://doi.org/10.3760/cma.j.cn112141-20211018-00603

[3] Bedaiwy MA, Alfaraj S, Yong P, et al. New developments in the medical treatment of endometriosis. Fertil Steril. 2017; 107(3):555-565. https://doi.org/10.1016/j.fertnstert.2016.12.025

[4] Giudice LC, Kao LC. Endometriosis[J]. Lancet, 2004, 9447(364): 1789-1799. https://doi.org/10.1016/S0140-6736(04)17403-5

[5] Perrone U, Evangelisti G, Laganà AS, et al. A review of phase II and III drugs for the treatment and management of endometriosis. Expert Opin Emerg Drugs. 2023; 28(4):333-351. https://doi.org/10.1080/14728214.2023.2296080

[6] Committee of Obstetrics and Gynaecology of the Chinese Society of Integrative Medicine. Guidelines for combined Chinese and Western medicine diagnosis and treatment of endometriosis. Chin J Integr Med. 2019; 39(10):1169-1176.

[7] Yang W. Progress of research on clinical application of Kuntai capsule in the treatment of gynaecological diseases. Drug Eval Res. 2015; 38(04):453-458.

[8] Wu CJ. Effect of kuntai capsule on follicular development, endometrium and ovulation in patients with ovulatory disorder infertility. China Pract Med. 2015; 10(18):10-12.

[9] Zhong WQ, QIAN HY. Analysis of efficacy and prognosis of applying Kuntai capsule combined with GnRH-a in patients with moderate to severe endometriosis. Chin J Tradit Chin Med. 2016; 34(12):3069-3072.

[10] Chen JM, Gao HY, Ding Y, et al. Efficacy and safety investigation of Kuntai capsule for the add-back therapy of gonadotropin releasing hormone agonist administration to endometriosis patients: a randomized, double-blind, blank- and tibolone-controlled study. Chin Med J (Engl). 2015; 128(4):427-432.

[11] Ru J, Li P, Wang J, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Chemin-. 2014; 6:13. https://doi.org/10.1186/1758-2946-6-13

[12] Kong X, Liu C, Zhang Z, et al. BATMAN-TCM 2.0:an enhanced integrative database for known and predicted interactions between traditional Chinese medicine ingredients and target proteins. Nucleic Acids Res. 2024; 52(D1):D1110-D1120.

[13] Ahmed SS, Ramakrishnan V. Systems biological approach of molecular descriptors connectivity: optimal descriptors for oral bioavailability prediction. PLoS One. 2012; 7(7):e40654. https://doi.org/10.1371/journal.pone.0040654

[14] Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019; 47(W1):W357-W364. https://doi.org/10.1093/nar/gkz382

[15] Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13(11):2498-2504. https://doi.org/10.1101/gr.1239303

[16] Szklarczyk D, Kirsch R, Koutrouli M, et al. The STRING database in 2023:protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023; 51(D1):D638-D646. https://doi.org/10.1093/nar/gkac1000

[17] Khan SA, Lee T. Network pharmacology and molecular docking-based investigations of Kochiae Fructus's active phytomolecules, molecular targets, and pathways in treating COVID-19. Front Microbiol. 2022; 13:972576. https://doi.org/10.3389/fmicb.2022.972576

[18] Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-2791. https://doi.org/10.1002/jcc.21256

[19] Van Der Spoel D, Lindahl E, Hess B, et al. GROMACS: fast, flexible, and free. J Comput Chem. 2005; 26(16):1701-1718. https://doi.org/10.1002/jcc.20291

[20] Hsin KY, Ghosh S, Kitano H. Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology. PLoS One. 2013; 8(12):e83922. https://doi.org/10.1371/journal.pone.0083922

[21] Yang L, Yu J, Zhang S, et al. Advances in the medical treatment of adolescent endometriosis. Minerva Pedia (Torino). 2023; 75(3):423-431. https://doi.org/10.23736/S2724-5276.21.06375-8

[22] Qi X, Guo Y, Sun L. Effects of Kuntai capsule on breast pain and vaginal bleeding in postmenopausal women. Pak J Pharm Sci. 2019;32(5(Special):2471-2476.

[23] Zhao XP, Ma XN, Guo YN. Investigation of the mechanism of Kuntai capsule in treating premature ovarian failure and menopausal syndrome based on network pharmacology and experimental study. World Tradit Chin Med. 2023; 18(14):1945-1951.

[24] Zheng YF, Wang JJ, FU CM, et al. Progress in the study of chemical composition and pharmacological effects of Scutellaria baicalensis. Chin Tradit Pat Med. 2016; 38(01):141-147.

[25] Meresman GF, Götte M, Laschke MW. Plants as source of new therapies for endometriosis: a review of preclinical and clinical studies. Hum Reprod Update. 2021; 27(2):367-392. https://doi.org/10.1093/humupd/dmaa039

[26] Zhong S, Liang Y, Wu Z, et al. Association between polymorphisms of cytokine genes and endometriosis: A comprehensive systematic review and meta-analysis. J Reprod Immunol. 2023; 158:103969. https://doi.org/10.1016/j.jri.2023.103969

[27] Mosbah A, Nabiel Y, Khashaba E. Interleukin-6, intracellular adhesion molecule-1, and glycodelin A levels in serum and peritoneal fluid as biomarkers for endometriosis. Int J Gynaecol Obstet. 2016; 134(3):247-251. https://doi.org/10.1016/j.ijgo.2016.01.018

[28] Jiang JY, Cheung CK, Wang Y, et al. Regulation of cell death and cell survival gene expression during ovarian follicular development and atresia. Front Biosci. 2003;8:d222-d237. https://doi.org/10.2741/949

[29] Liu MJ, Deng YS, Ma Y. Regulation of endometrial stromal cell invasion and autophagy in endometriosis by miR-34a-5p targeting AKT 1 gene. J China Med Univ. 2020; 49(09):776-782.

[30] Mustafa Rizvi SH, Shao D, Tsukahara Y, et al. Oxidized GAPDH transfers S-glutathionylation to a nuclear protein Sirtuin-1 leading to apoptosis. Free Radic Biol Med. 2021; 174:73-83. https://doi.org/10.1016/j.freeradbiomed.2021.07.037

[31] Kang N, Zhang X, Wang Z, et al. Validation of a one-step genomics-based molecular classifier for endometrial carcinoma in a large Chinese population. Pathol Res Pr. 2024; 254:155152.

[32] Bi X, Liu S, Liu D, et al. Elucidating the role of Brain-Derived Neurotrophic Factor (BDNF) and its receptor Tyrosine Receptor Kinase B (TrkB) in the development and symptoms of endometriosis. Int J Neurosci. 2025; 135(1):63-69. https://doi.org/10.1080/00207454.2023.2285709

[33] Zheng R, Du X, Lei Y. Correlations between endometriosis, lipid profile, and estrogen levels. Med (Baltim). 2023; 102(29):e34348. https://doi.org/10.1097/MD.0000000000034348

[34] Zhong R, Ma A, Zhu J, et al. Kuntai capsule inhibited endometriosis via inducing apoptosis in a rat model. Evid Based Complement Altern Med. 2016; 2016:5649169. https://doi.org/10.1155/2016/5649169