Network pharmacology and molecular docking of Phaleria macrocarpa (Scheff.) Boerl. bioactive compounds involved in endometriosis pathway

Context: Endometriosis is the presence of endometrial glands and stromal lesions outside the uterus. Aims: To investigate the network pharmacology and molecular docking of Phaleria macrocarpa bioactive compounds on selected endometriosis pathways.

P. macrocarpa compounds were obtained from PubChem. The compounds were analyzed for their potential using the WAY2DRUG PASS prediction. Protein targets were predicted using the Comparative Toxicogenomic Database (CTD), STITCH, and Open Target databases. The pharmacology network analysis was conducted using STRING. Molecular docking analysis was performed between tolfenamic acid, naringenin, eriodictyol, 5-O-methylgenistein, and 8-prenylnaringenin against postaglandin-endoperoxide synthase 2/cyclooxygenase-2 (PTGS2/COX-2) and progesterone receptor (PGR) protein using AutoDock Vina integrated into PyRx v.0.9.8. The visualization was performed using BioVia Discovery Studio 2019 software.

For the PTGS/COX-2 pathway, the compounds that have the highest affinity for interaction to occur are tolfenamic acid and naringenin. Against PGR, the phytochemicals with the highest interaction affinity are naringenin and 8-prenylnaringenin.

According to the molecular docking results, P. macrocarpa compounds are predicted to have activity as PTGS2/COX-2 inhibitors, especially (±)-naringenin and eriodictyol. Narigenin and 8-prenylnaringenin showed activity to PGR. Compared to 8-prenylnarigenin, naringenin binds more strongly to PGRs.

angiogenesis; endometriosis; inflammation; pathomechanisms; proliferation. Resumen Contexto: La endometriosis se define como la presencia de glándulas endometriales y lesiones estromales fuera del útero. Objetivos: Investigar la farmacología en red y la unión molecular de los compuestos bioactivos de Phaleria macrocarpa en vías específicas de la endometriosis. Métodos: Los compuestos de P. macrocarpa se obtuvieron de PubChem. Se analizó el potencial de los compuestos mediante la predicción WAY2DRUG PASS. Las dianas proteicas se predijeron utilizando las bases de datos Comparative Toxicogenomic Database (CTD), STITCH y Open Target. El análisis de redes farmacológicas se realizó con STRING. Se realizó un análisis de acoplamiento molecular entre ácido tolfenámico, naringenina, eriodictiol, 5-O-metilgenisteína y 8-prenilnaringenina frente a la proteína postraglandina-endoperóxido sintasa 2/ciclooxigenasa-2 (PTGS2/COX-2) y el receptor de progesterona (PGR) utilizando AutoDock Vina integrado en PyRx v.0.9.8. La visualización se realizó con el software BioVia Discovery Studio 2019. Resultados: En la vía PTGS/COX-2, los compuestos con mayor afinidad para la interacción son el ácido tolfenámico y la naringenina. Frente al PGR, los fitoquímicos con mayor afinidad de interacción son la naringenina y la 8-prenilnaringenina. Conclusiones: Según los resultados del acoplamiento molecular, se predice que los compuestos de P. macrocarpa tienen actividad como inhibidores de PTGS2/COX-2, especialmente la (±)-naringenina y el eriodictiol. La narigenina y la 8-prenilnaringenina mostraron actividad sobre los PGR. En comparación con la 8-prenilnarigenina, la naringenina se une con mayor fuerza a los PGR. Palabras Clave: angiogénesis; endometriosis; inflamación; patomecanismos; proliferación. Citation Format: Sutrisno S, Maharani M (2025) Network pharmacology and molecular docking of Phaleria macrocarpa (Scheff.) Boerl. bioactive compounds involved in endometriosis pathway. J Pharm Pharmacogn Res 13(s1): S140–S152. https://doi.org/10.56499/jppres24.2238_13.s1.140

Agarwal A, Mulgund A, Hamada A, Chyatte MR (2015) A unique view on male infertility around the globe. Reprod Biol Endocrinol 13: 37. https://doi.org/10.1186/s12958-015-0032-1 Ahmad R, Mazlan MKN, Aziz AFA, Gazzali AM, Rawa MSA, Wahab HA (2023) Phaleria macrocarpa (Scheff.) Boerl.: An updated review of pharmacological effects, toxicity studies, and separation techniques. Saudi Pharm J 31(6): 874–888. https://doi.org/10.1016/j.jsps.2023.04.006 Altaf R, Asmawi MB, Dewa A, Sadikun A, Umar M (2013) Phytochemistry and medicinal properties of Phaleria macrocarpa (Scheff.) Boerl. extracts. Pharmacogn Rev 7(13): 73–80. https://doi.org/10.4103/0973-7847.112853 Chen S, Ding Y, Tao W, Zhang W, Liang T, Liu C (2012) Naringenin inhibits TNF-α induced VSMC proliferation and migration via induction of HO-1. Food Chem Toxicol 50(9): 3025–3031. https://doi.org/10.1016/j.fct.2012.06.006 Deng Z, Hassan S, Rafiq M, Li H, He Y, Cai Y, Kang X, Liu Z, Yan T (2020) Pharmacological activity of eriodictyol: the major natural polyphenolic flavanone. Evid Based Complement Alternat Med 2020: 6681352. https://doi.org/10.1155/2020/6681352 Febriani A, Sutrisno S, Irwanto Y, Baihaqi I, Wiyasa IWA, Rahardjo B (2022) Effect of Phaleria macrocarpa extract on NF-kB, MMP-2, and MMP-9 expression in endometriosis mice model. Asian J Heal Res 1(3): 4-10. https://doi.org/10.55561/ajhr.v1i3.35 Filimonov DA, Lagunin AA, Gloriozova TA, Rudik AV, Druzhilovskii DS, Pogodin PV, Poroikov VV (2014) Prediction of the biological activity spectra of organic compounds using the pass online web resource. Chem Heterocycl Comp 50: 444–457. https://doi.org/10.1007/s10593-014-1496-1 Hämäläinen M, Nieminen R, Asmawi M, Vuorela P, Vapaatalo H, Moilanen E (2011) Effects of flavonoids on prostaglandin E2 production and on COX-2 and mPGES-1 expressions in activated macrophages. Planta Med 77(13): 1504–1511. https://doi.org/10.1055/s-0030-1270762 Hämäläinen M, Nieminen R, Vuorela P, Heinonen M, Moilanen E (2007) Anti-inflammatory effects of flavonoids: Genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-κB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-κB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediators Inflam 2007: 45673. https://doi.org/10.1155/2007/45673 Hendra R, Ahmad S, Oskoueian E, Sukari A, Shukor MY (2011) Antioxidant, anti-inflammatory and cytotoxicity of Phaleria macrocarpa (Boerl.) Scheff fruit. BMC Complement Altern Med 11: 110. https://doi.org/10.1186/1472-6882-11-110 Irwanto Y, Wiyono T, Wardani K (2023) The effect of flavonoid extract from Phaleria macrocarpa to proliferating factors (MMP-1, MMP-3, MMP-7) in endometriosis mice model. Asian J Heal Res 2(3): 25–30. https://doi.org/10.55561/ajhr.v2i3.102 Jouhari S, Mohammadzadeh A, Soltanghoraee H, Mohammadi Z, Khazali S, Mirzadegan E, Lakpour N, Fatemi F, Zafardoust S, Mohazzab A, Naderi MM (2018) Effects of silymarin, cabergoline and letrozole on rat model of endometriosis. Taiwanese J Obstet Gynecol 57(6): 830–835. https://doi.org/10.1016/j.tjog.2018.10.011 Kapoor R, Sirohi VK, Gupta K, Dwivedi A (2019) Naringenin ameliorates progression of endometriosis by modulating Nrf2/Keap1/HO1 axis and inducing apoptosis in rats. J Nutr Biochem 70: 215–226. https://doi.org/10.1016/j.jnutbio.2019.05.003 Klemmt PAB, Starzinski-Powitz A (2018) Molecular and cellular pathogenesis of endometriosis. Curr Womens Health Rev 14(2): 106–116. https://doi.org/10.2174/1573404813666170306163448 La Rosa P, Pellegrini M, Totta P, Acconcia F, Marino M (2014) Xenoestrogens alter estrogen receptor (ER) α intracellular levels. PLoS ONE 9(2): e88961. https://doi.org/10.1371/journal.pone.0088961 Lee JK (2011) Anti-inflammatory effects of eriodictyol in lipopolysaccharide-stimulated RAW 264.7 murine macrophages. Arch Pharm Res 34: 671–679. https://doi.org/10.1007/s12272-011-0418-3 Macer ML, Taylor HS (2012) Endometriosis and infertility. Obstet Gynecol Clin North Am 39(4): 535–549. https://doi.org/10.1016/j.ogc.2012.10.002 Maharani M, Lajuma L, Yuniwati C, Veri N, Sutrisno S (2023) Phaleria macrocarpa for endometriosis treatment: A review. J Med Pharm Allied Sci 12(1): 5582–5587. https://doi.org/10.55522/jmpas.V12I1.4232 Maharani M, Lajuna L, Yuniwati C, Sabrida O, Sutrisno S (2021) Phytochemical characteristics from Phaleria macrocarpa and its inhibitory activity on the peritoneal damage of endometriosis. J Ayurveda Integr Med 12(2): 229–233. https://doi.org/10.1016/j.jaim.2020.06.002 Maharani M, Sutrisno S (2022) Phaleria macrocarpa flavonoid as a potent MMP-1 inhibitor for endometriosis therapy: In silico study. Asian J Heal Res 1(2): 7–11. https://doi.org/10.55561/ajhr.v1i2.24 Mendes LF, Gaspar VM, Conde TA, Mano JF, Duarte IF (2019) Flavonoid-mediated immunomodulation of human macrophages involves key metabolites and metabolic pathways. Sci Rep 9: 14906. https://doi.org/10.1038/s41598-019-51113-z Nafisah W, Fatchiyah F, Widyananda MH, Christina YI, Rifa’i M, Widodo N, Djati MS (2022) Potential of bioactive compound of Cyperus rotundus L. rhizome extract as inhibitor of PD-L1/PD-1 interaction: An in silico study. Agr Nat Resour 56(4): 751–760. https://doi.org/10.34044/j.anres.2022.56.4.09 Orlando BJ, Malkowski MG (2016) Substrate-selective inhibition of cyclooxygenase-2 by fenamic acid derivatives is dependent on peroxide tone. J Biol Chem 291(29): 15069–15081. https://doi.org/10.1074/jbc.M116.725713 Parasar P, Ozcan P, Terry KL (2017) Endometriosis: Epidemiology, diagnosis and clinical management. Curr Obstet Gynecol Rep 6: 34–41. https://doi.org/10.1007/s13669-017-0187-1 Pohjanvirta R, Nasri A (2022) The potent phytoestrogen 8-prenylnaringenin: A friend or a foe? Int J Mol Sci 23(6): 3168. https://doi.org/10.3390/ijms23063168 Saunders PTK, Horne AW (2021) Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell 184(11): 2807–2824. https://doi.org/10.1016/j.cell.2021.04.041 Sim KS, Park S, Seo H, Lee S-H, Lee H-S, Park Y, Kim JH (2022) Comparative study of estrogenic activities of phytoestrogens using OECD in vitro and in vivo testing methods. Toxicol Appl Pharmacol 434: 115815. https://doi.org/10.1016/j.taap.2021.115815 Sutrisno S, Maharani M (2024) Genistein ameliorated vascular endothelial growth factor-A (VEGF-A) and estrogen receptor-alpha (ER-α) in endometriosis mice model, in vivo and in silico. ScientificWorldJournal 2024: 5338212. https://doi.org/10.1155/2024/5338212 Suttana W, Mankhetkorn S, Poompimon W, Palagani A, Zhokhov S, Gerlo S, Haegeman G, Berghe WV (2010) Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols. Mol Cancer 9: 99. https://doi.org/10.1186/1476-4598-9-99 Tjandrawinata R, Tandrasasmita O, Sutanto A, Arifin P (2015) Anti-inflammatory, antiangiogenic, and apoptosis-inducing activity of DLBS1442, a bioactive fraction of Phaleria macrocarpa, in a RL95-2 cell line as a molecular model of endometriosis. Int J Womens Health 2015: 161-169. https://doi.org/10.2147/IJWH.S74552 Vania D, Hutagalung AF (2023) Plasma exchange as a rescue therapy in Weil’s disease with severe hyperbilirubinemia, acute renal failure, and multidrug-resistant organism co-infection: A rare case in critical care setting. J Biomed Transl Res 9(2): 82–87. https://doi.org/10.14710/jbtr.v9i2.17625 Wang X, Deng R, Dong J, Huang L, Li J, Zhang B (2020) Eriodictyol ameliorates lipopolysaccharide-induced acute lung injury by suppressing the inflammatory COX-2/NLRP3/NF-κB pathway in mice. J Biochem Mol Toxicol 34(3): e22434. https://doi.org/10.1002/jbt.22434 Wilhelm H, Wessjohann LA (2006) An efficient synthesis of the phytoestrogen 8-prenylnaringenin from xanthohumol by a novel demethylation process. Tetrahedron 62(29): 6961–6966. https://doi.org/10.1016/j.tet.2006.04.060 Xu Z, Huang B, Liu J, Wu X, Luo N, Wang X, Zheng X, Pan X (2018) Combinatorial anti-proliferative effects of tamoxifen and naringenin: The role of four estrogen receptor subtypes. Toxicology 410: 231–246. https://doi.org/10.1016/j.tox.2018.08.013 Yap C, Furness S, Farquhar C (2000) Pre and post operative medical therapy for endometriosis surgery. Cochrane Database Syst Rev (2): CD003678. https://doi.org/10.1002/14651858.CD003678 © 2025 Journal of Pharmacy & Pharmacognosy Research