Network Pharmacology and Molecular Docking Elucidate Key Targets and Multi-Pathway Modulation in the Antidiabetic Action of Momordica charantia L.
DOI:
https://doi.org/10.11113/bioprocessing.v4n2.86Keywords:
Momordica charantia L, Type 2 diabetes mellitus, Network pharmacology, Molecular dockingAbstract
Type 2 diabetes mellitus (T2DM) is characterised by hyperglycaemia resulting from insulin resistance, diminished tissue sensitivity to insulin, impaired beta-cell function, or dysregulated glucagon secretion. It is a major public health concern in Malaysia, affecting nearly one in five adults. As there is currently no definitive cure, the disease management of T2DM relies on sustained lifestyle and pharmacological intervention. Momordica charantia L. (bitter gourd) is traditionally recognised for its antidiabetic properties, yet its key therapeutic targets and mechanisms of action remain incompletely understood. Therefore, this study employed an in silico approach to investigate the pharmacokinetic properties and antidiabetic activity of six key bioactive compounds in M. charantia, including stigmasterol glucoside (SG), beta-sitosterol glucoside (BSG), diosgenin, oleanolic acid, stigmasterol, and beta-sitosterol. The present results showed that all six compounds satisfied Lipinski’s Rule of Five, indicating good oral bioavailability. In addition, SG, BSG, and diosgenin were found to be non-toxic with a predicted LD50 of 8000 mg/kg, while oleanolic acid, stigmasterol, and beta-sitosterol showed moderate toxicity (LD50 between 890-2000 mg/kg). Network pharmacology analysis identified 97 potential compound targets associated with T2DM. KEGG and gene ontology enrichment analysis linked these targets to critical pathways including insulin signalling, insulin resistance, and endocrine resistance. In addition, molecular docking analysis further demonstrated strong binding affinities of the metabolites with key targets including alpha-amylase, MAPK8, CES1, PPARG, and GSK3B. Collectively, these findings indicated that M. charantia metabolites exert antidiabetic effects through multi‑target and multi‑pathway modulation. This work may provide a systems‑level mechanistic foundation for the traditional use of M. charantia and supporting its potential as a source for novel T2DM therapeutics.
References
Cao, Z., Wang, X., Zeng, Z., Yang, Z., Lin, Y., Sun, L., Lu, Q., & Fan, G. (2024). The improvement of modified Si-Miao granule on hepatic insulin resistance and glycogen synthesis in type 2 diabetes mellitus involves the inhibition of TNF-α/JNK1/IRS-2 pathway: Network pharmacology, molecular docking, and experimental validation. Chinese Medicine, 19, 1–20.
https://doi.org/10.1186/s13020-024-00997-9
Dominguez, E., Galmozzi, A., Chang, J. W., Hsu, K.-L., Pawlak, J., Li, W., Godio, C., Thomas, J., Partida, D., Niessen, S., O’Brien, P. E., Russell, A. P., Watt, M. J., Nomura, D. K., Cravatt, B. F., & Saez, E. (2014). Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes. Nature Chemical Biology, 10(2), 113–121. https://doi.org/10.1038/nchembio.1429
Fang, F., Zhang, X., & Fang, Y. (2024). Diosgenin inhibits proliferation and migration of ovarian cancer cells and induce apoptosis via upregulation of PTEN. Chemical Biology & Drug Design, 103(3), e14459. https://doi.org/10.1111/cbdd.14459
Friedrichsen, M., Poulsen, P., Wojtaszewski, J., Hansen, P. R., Vaag, A., & Rasmussen, H. B. (2013). Carboxylesterase 1 gene duplication and mRNA expression in adipose tissue are linked to obesity and metabolic function. PLoS One, 8(2), e56861. https://doi.org/10.1371/journal.pone.0056861
Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K. B., Ostolaza, H., & Martín, C. (2020). Pathophysiology of Type 2 Diabetes Mellitus. International Journal of Molecular Sciences, 21(17), 6275.
https://doi.org/10.3390/ijms21176275
Lee, J., Jung, K., Kim, Y. S., & Park, D. (2007). Diosgenin inhibits melanogenesis through the activation of phosphatidylinositol-3-kinase pathway (PI3K) signaling. Life Sciences, 81(3), 249–254. https://doi.org/10.1016/j.lfs.2007.05.009
Li, C., Tang, S., Hu, T., Zhou, C., Chen, Y., Hu, Z., Pan, J., Chen, J., & Wang, Y. (2025). Exploring the potential mechanism of action of Wutou-Guizhi decoction in the treatment of rheumatoid arthritis through network pharmacology analysis. Computational Biology and Chemistry, 115, 108314. https://doi.org/10.1016/j.compbiolchem.2024.108314
MacAulay, K., & Woodgett, J. R. (2008). Targeting glycogen synthase kinase-3 (GSK-3) in the treatment of Type 2 diabetes. Expert Opinion on Therapeutic Targets, 12(10), 1265–1274.
https://doi.org/10.1517/14728222.12.10.1265
Nazir, R., Bhat, I. A., Qadir, R. U., & Pandey, D. K. (2025). Exploring the diosgenin and β-sitosterol content in different populations of Dioscorea deltoidea Wall. ex Griseb: Insights into their antidiabetic activity and genotoxicity. Journal of Ethnopharmacology, 352, 120230. https://doi.org/10.1016/j.jep.2025.120230
Richter, E., Geetha, T., Burnett, D., Broderick, T. L., & Babu, J. R. (2023). The effects of Momordica charantia on Type 2 Diabetes Mellitus and Alzheimer’s Disease. International Journal of Molecular Sciences, 24(5), 4643. https://doi.org/10.3390/ijms24054643
Ring, D. B., Johnson, K. W., Henriksen, E. J., Nuss, J. M., Goff, D., Kinnick, T. R., Ma, S. T., Reeder, J. W., Samuels, I., Slabiak, T., Wagman, A. S., Hammond, M.-E. W., & Harrison, S. D. (2003). Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes, 52(3), 588–595. https://doi.org/10.2337/diabetes.52.3.588
Sarhangi, N., Sharifi, F., Hashemian, L., Hassani Doabsari, M., Heshmatzad, K., Rahbaran, M., Jamaldini, S. H., Aghaei Meybodi, H. R., & Hasanzad, M. (2020). PPARG (Pro12Ala) genetic variant and risk of T2DM: A systematic review and meta-analysis. Scientific Reports, 10(1), 12764. https://doi.org/10.1038/s41598-020-69363-7
Shi, L., Li, L.-J., Sun, X.-Y., Chen, Y.-Y., Luo, D., He, L.-P., Ji, H.-J., Gao, W.-P., & Shen, H.-X. (2024). Er-Dong-Xiao-Ke decoction regulates lipid metabolism via PPARG-mediated UCP2/AMPK signaling to alleviate diabetic meibomian gland dysfunction. Journal of Ethnopharmacology, 333, 118484. https://doi.org/10.1016/j.jep.2024.118484
Shin, H., Schneeweiss, S., Glynn, R. J., & Patorno, E. (2021). Trends in first-line glucose-lowering drug use in adults with Type 2 Diabetes in light of emerging evidence for SGLT-2i and GLP-1RA. Diabetes Care, 44(8), 1774–1782. https://doi.org/10.2337/dc20-2926
Song, Y.-Q., Jin, Q., Wang, D.-D., Hou, J., Zou, L.-W., & Ge, G.-B. (2021). Carboxylesterase inhibitors from clinically available medicines and their impact on drug metabolism. Chemico-Biological Interactions, 345, 109566. https://doi.org/10.1016/j.cbi.2021.109566
Wang, D.-D., Wang, Z.-Z., Liu, W.-C., Qian, X.-K., Zhu, Y.-D., Wang, T.-G., Pan, S.-M., & Zou, L.-W. (2024). Pyrazolone compounds could inhibit CES1 and ameliorates fat accumulation during adipocyte differentiation. Bioorganic Chemistry, 150, 107536. https://doi.org/10.1016/j.bioorg.2024.107536
Wang, M., Tan, J., He, X., Chen, Y., Qiu, G., & Yang, M. (2025). Positive feedback loop between MAPK and aquaporin 7 regulates autophagy and apoptosis induced by palmitate in RIN‐m5f cells. FEBS Open Bio, 15(6), 972–984.
