A molecular docking insight: Phyllanthus niruri L. constituents targeting MMP-9 for angiogenesis inhibition and IL-1beta for antiinflammatory action in endometriosis therapy

Eka Tri Wulandari; Soetrisno; Bambang  Purwanto; Reviono; Yogi  Ertanto; Joko  Sunowo

doi:10.14719/pst.3224

Authors

Eka Tri Wulandari Doctoral Program of Medical Sciences, Faculty of Medicine, Universitas Sebelas Maret, Surakarta 57126, Indonesia https://orcid.org/0000-0003-4015-9449
Soetrisno Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Sebelas Maret—USM Hospital, Surakarta 57126, Indonesia https://orcid.org/0000-0003-0404-3676
Bambang Purwanto Department of Internal Medicine, Faculty of Medicine, Universitas Sebelas Maret—USM Hospital, Surakarta 57126, Indonesia https://orcid.org/0000-0002-5494-4571
Reviono Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Sebelas Maret—USM Hospital, Surakarta 57126, Indonesia https://orcid.org/0000-0001-5463-1850
Yogi Ertanto Faculty of Military Pharmacy, Universitas Pertahanan Republik Indonesia, Bogor 16810, Indonesia https://orcid.org/0000-0001-6739-9608
Joko Sunowo Department of Pharmacy Study Program, Faculty of Health Sciences, Malahayati University, Lampung 35152, Indonesia https://orcid.org/0000-0001-5799-0912

DOI:

https://doi.org/10.14719/pst.3224

Keywords:

Endometriosis , Phyllanthus niruri , molecular docking, MMP-9 , IL-1β

Abstract

Endometriosis, characterized by inflammatory lesions resembling endometrium outside the uterine cavity, induces chronic inflammation, anatomical changes and persistent pain. The expression of Interleukin 1beta (IL-1beta) is significantly associated with endometriosis, contributing to inflammatory process and fertility issues. Matrix metalloproteinase 9 (MMP-9) is crucial in the adhesion and angiogenesis of endometrial tissue. This study investigates the potential of Phyllanthus niruri L. in inhibiting MMP-9 and IL-1beta through molecular docking analysis.

Molecular docking was performed using Discovery Studio Visualizer, Open Babel, PyRx and AutoDock Vina. The inhibitory activities of bioactive compounds on MMP-9 and IL-1beta were predicted. Biological activity and cytotoxicity were assessed using PASS and CLC-Pred respectively. Kaempferol and quercetin from P. niruri exhibited significant MMP-9 expression inhibitory activity. Search Tool for Interacting Chemicals (STITCH) analysis revealed interactions of quercetin and galangin with specific proteins involved in pathways related to endometriosis. Biological activity analysis indicated that quercetin, kaempferol, herbacetin and galangin show potential as MMP -9 expression inhibitors. CLC-Pred analysis suggested high cytotoxicity of kaempferol against glioma.

Molecular docking results showed quercetin's potential as an MMP-9 inhibitor and galangin's potential as an IL-1 beta inhibitor. These findings support the therapeutic potential of P. niruri for endometriosis, providing insights for further research in developing innovative therapies targeting endometriosis-related inflammation and angiogenesis.

Downloads

Download data is not yet available.

References

Wang Y, Nicholes K, Shih IM. The origin and pathogenesis of endometriosis. Annu Rev Pathol …[Internet]. 2020; Available from: https://www.annualreviews.org/doi/abs/10.1146/annurev-pathmechdis-012419-032654

Asghari S, Valizadeh A, Aghebati-Maleki L, Nouri M, Yousefi M. Endometriosis: Perspective, lights and shadows of etiology. Biomed Pharmacother. 2018 June;106:163-74. https://doi.org/10.1016/j.biopha.2018.06.109

Lamceva J, Uljanovs R, Strumfa I. The main theories on the pathogenesis of endometriosis. Int J Mol Sci. 2023;24(5). https://doi.org/10.3390/ijms24054254

Missmer SA, Tu FF, Agarwal SK. Impact of endometriosis on life-course potential: A narrative review [Internet]. International Journal of General Medicine. ncbi.nlm.nih.gov; 2021. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7800443/

Soliman AM, Surrey E, Bonafede M, Nelson JK, Castelli-Haley J. Real-World evaluation of direct and indirect economic burden among endometriosis patients in the united states. Adv Ther [Internet]. 2018;35(3):408-23. Available from: https://doi.org/10.1007/s12325-018-0667-3

Swift B, Taneri B, Becker CM, Basarir H, Naci H, Missmer SA et al. Prevalence, diagnostic delay and economic burden of endometriosis and its impact on quality of life: Results from an Eastern Mediterranean population. Eur J Public Health. 2024;34(2):244-52. https://doi.org/10.1093/eurpub/ckad216

Peng B, Alotaibi FT, Sediqi S, Bedaiwy MA, Yong PJ. Role of interleukin-1? in nerve growth factor expression, neurogenesis and deep dyspareunia in endometriosis. Hum Reprod. 2021;35(4):901-12. https://doi.org/10.1093/humrep/deaa017

Sikora J, Smycz-Kuba?ska M, Mielczarek-Palacz A, Kondera-Anasz Z. Abnormal peritoneal regulation of chemokine activation—The role of IL-8 in pathogenesis of endometriosis. Am J Reprod Immunol. 2017;77(4):1-8. https://doi.org/10.1111/aji.12622

Matsuzaki S, Gremeau AS, Pouly JL. Impaired pathogen-induced autophagy and increased IL-1? and TNF? release in response to pathogenic triggers in secretory phase endometrial stromal cells of endometriosis patients. Reprod Biomed Online. 2020;41(5):767-81. https://doi.org/10.1016/j.rbmo.2020.06.011

Zheng W, Cao L, Xu Z, Ma Y, Liang X. Anti-angiogenic alternative and complementary medicines for the treatment of endometriosis: A review. 2018;2018. https://doi.org/10.1155/2018/4128984

Ke J, Ye J, Li M, Zhu Z. The role of matrix metalloproteinases in endometriosis?: A potential target. 2021;1-16.

Hasan M, Safarianti S, Ramadhani AF, Khilfi S, Suryawati S, Husna F. Bioactive compounds and in vitro evaluation of Phyllanthus niruri extract as antioxidant and antimicrobial activities. Trends Sci. 2024;21(2). https://doi.org/10.48048/tis.2024.7130

Jeevani Maheshika Dahanayake PKP, Galappaththy P, Arawwawala AM. A mini-review on therapeutic potentials of Phyllanthus niruri Linn. 2020;4(3):101-08.

Kaur N, Kaur B, Sirhindi G. Phytochemistry and pharmacology of Phyllanthus niruri L.: A review. Phyther Res. 2017;31(7):980-1004. https://doi.org/10.1002/ptr.5825

Cholet J, Decombat C, Delort L, Gainche M, Berry A, Ogeron C et al. Potential anti-inflammatory and chondroprotective effect of Luzula sylvatica. Int J Mol Sci. 2023;24(1). https://doi.org/10.3390/ijms24010127

Rashidi Z, Khosravizadeh Z, Talebi A. Overview of biological effects of Quercetin on ovary. Phyther … [Internet]. 2021; Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.6750

de Morais EF, de Oliveira LQR, Farias Morais HG de, Souto Medeiros MR de, Freitas R de A, Rodini CO et al. The anticancer potential of Kaempferol: A systematic review based on in vitro studies. Cancers (Basel). 2024;16(3):1-30. https://doi.org/10.3390/cancers16030585

Puthanveedu V, Shameera Ahamed TK, Muraleedharan K. Theoretical insights into Zn2+ chelated complexes of herbacetin for the application in Alzheimer’s disease. Chem Phys Impact [Internet]. 2023;6:100163. Available from: https://doi.org/10.1016/j.chphi.2023.100163

Jomova K, Cvik M, Orolinova T, Y Alomar S, H Alwasel S, Aldahmash W et al. Antioxidant versus prooxidant properties of the flavonoid, galangin: ROS scavenging activity, flavonoid-DNA interaction, copper-catalyzed Fenton reaction and DNA damage study. J Agric Food Res [Internet]. 2024;16:101112. Available from: https://doi.org/10.1016/j.jafr.2024.101112

Zheng Q han, Du L yun, Zhao Y, Zhang Z, Piao S lan, Wang Y hang et al. Mechanism of Rhodiola rosea–Euonymus alatus drug pair against rheumatoid arthritis: Network pharmacology and experimental validation. Immunity, Inflamm Dis. 2023;11(12):1-20. https://doi.org/10.1002/iid3.1127

Machairiotis N, Vasilakaki S, Thomakos N. Inflammatory mediators and pain in endometriosis: A systematic review. Biomedicines. 2021;9(1):1-18. https://doi.org/10.3390/biomedicines9010054