{"paper_id":"1ad3268a-6324-4ba4-9819-76888ddb070f","body_text":"J. Pharm. Pharmacogn. Res., vol. 14, no. 3, Article ID 2658, May-Jun 2026.\nDOI: https://doi.org/10.56499/jppres_14.3.2658Original Article\n5-O-Methylgenistein of Phaleria macrocarpa (Scheff.) Boerl. revealed as a potential therapeutic compound for endometriosis\n[5-O-Metilgenisteína de Phaleria macrocarpa (Scheff.) Boerl. revelado como un posible compuesto terapéutico para la endometriosis]\nSutrisno Sutrisno1*, Maharani Maharani2\n1Department of Obstetrics and Gynaecology/Master of Midwifery, Faculty of Medicine, Universitas Brawijaya/ Saiful Anwar General Hospital, Malang, East Java, Indonesia.\n2Department of Midwifery, Polytechnic of Health-Ministry of Health, Aceh, Indonesia.\n*E-mail: snospog.fk@ub.ac.id\nAbstract\nContext: Endometriosis is a chronic estrogen-dependent inflammatory disorder associated with pelvic pain and infertility. Flavonoids from Phaleria macrocarpa have been reported to exhibit anti-inflammatory activity; however, their molecular mechanisms relevant to endometriosis remain insufficiently characterized.\nAims: To predict biological activities of selected P. macrocarpa flavonoids and to explore potential protein–ligand interactions with endometriosis-relevant targets using molecular docking.\nMethods: Six flavonoids (eriodictyol, glycitin, 5-O-methylgenistein, catechin 7-O-β-D-xyloside, 8-prenylnaringenin, and naringenin) were assessed using the PASS web server to estimate biological activity probabilities (Pa/Pi). The compound with the highest predicted anti-inflammatory probability (Pa > 0.7) was selected for docking against cyclooxygenase-2 (COX-2), estrogen receptor (ER), AKT, aryl hydrocarbon receptor (AHR), and caspase-3 using Molegro Virtual Docker. Docking protocol validation was performed by redocking co-crystallized ligands and evaluating RMSDs.\nResults: PASS prediction indicated that all compounds exhibited potential anti-inflammatory activity (Pa > Pi), with 5-O-methylgenistein showing the highest confidence prediction (Pa = 0.838). Docking analysis suggested that 5-O-methylgenistein can occupy the binding sites of COX-2, ER, AKT, and AHR, showing comparable interaction patterns and overlapping residues with those of reference ligands, as indicated by software-derived scores. Redocking validation confirmed the acceptable reproduction of the pose (RMSD ≤ 2.0 Å).\nConclusions: 5-O-methylgenistein was identified as a promising candidate for further investigation. The predicted interactions support hypotheses related to inflammation- and hormone-associated pathways in endometriosis; however, these findings are based on computational models and require experimental validation to confirm biological activity and therapeutic relevance.\nKeywords: AKT; cyclooxygenase-2; endometriosis; molecular docking; Phaleria macrocarpa; phytoestrogens.\nResumen\nContexto: La endometriosis es un trastorno inflamatorio crónico dependiente de estrógenos asociado con dolor pélvico e infertilidad. Se ha informado que los flavonoides de Phaleria macrocarpa exhiben actividad antiinflamatoria; sin embargo, sus mecanismos moleculares relevantes para la endometriosis aún no están suficientemente caracterizados.\nObjetivos: Predecir las actividades biológicas de flavonoides seleccionados de P. macrocarpa y explorar posibles interacciones proteína-ligando relevantes para la endometriosis mediante acoplamiento molecular.\nMétodos: Se evaluaron seis flavonoides (eriodictiol, glicitina, 5-O-metilgenisteína, catequina 7-O-β-D-xilósido, 8-prenilnaringenina y naringenina) mediante el servidor web PASS para estimar las probabilidades de actividad biológica (Pa/Pi). El compuesto con la mayor probabilidad antiinflamatoria prevista (Pa > 0,7) se seleccionó para acoplarse a la ciclooxigenasa-2 (COX-2), el receptor de estrógeno (ER), AKT, el receptor de aril hidrocarburo (AHR) y la caspasa-3 mediante Molegro Virtual Docker. La validación del protocolo de acoplamiento se realizó mediante el reacoplamiento de ligandos cocristalizados y la evaluación del RMSD.\nResultados: La predicción PASS indicó que todos los compuestos exhibieron actividad antiinflamatoria potencial (Pa > Pi), y la 5-O-metilgenisteína mostró la predicción de confianza más alta (Pa = 0,838). El análisis de acoplamiento sugirió que la 5-O-metilgenisteína puede ocupar los sitios de unión de COX-2, ER, AKT y AHR, mostrando patrones de interacción comparables y residuos superpuestos con los de los ligandos de referencia, como lo indican las puntuaciones del software. La validación del reacoplamiento confirmó una reproducción aceptable de la pose (RMSD ≤ 2,0 Å).\nConclusiones: La 5-O-metilgenisteína fue identificada como una candidata prometedora para investigación adicional. Las interacciones previstas respaldan hipótesis relacionadas con las vías asociadas a la inflamación y con las hormonas en la endometriosis; sin embargo, estos hallazgos se basan en modelos computacionales y requieren validación experimental para confirmar su actividad biológica y su relevancia terapéutica.\nPalabras Clave: acoplamiento molecular; AKT; ciclooxigenasa-2; endometriosis; fitoestrógenos; Phaleria macrocarpa.\nCitation Format: Sutrisno S, Maharani M (2026) 5-O-Methylgenistein of Phaleria macrocarpa (Scheff.) Boerl. revealed as a potential therapeutic compound for endometriosis. J Pharm Pharmacogn Res 14(3): 2658. https://doi.org/10.56499/jppres_14.3.2658\nReferences\nAblimit T, Tursun G, Zhang Y, Abduxkur G, Abdurexit G, Abliz G (2022) Inositol monophosphatase 2 promotes epithelial ovarian cancer cell proliferation and migration by regulating the AKT/mTOR signaling pathway. Exp Ther Med 24(5): 668. https://doi.org/10.3892/etm.2022.11604\nAgarwal N, Subramanian A (2010) Endometriosis - Morphology, clinical presentations and molecular pathology. J Lab Physicians 2(1): 1-9: https://doi.org/10.4103/0974-2727.66699\nAhmed Juvale II, Abdul Hamid AA, Abd Halim KB, Che Has AT (2022) P-glycoprotein: New insights into structure, physiological function, regulation and alterations in disease. Heliyon 8(6): e09777. https://doi.org/10.1016/j.heliyon.2022.e09777\nAlara OR, Olalere OA (2016) A critical overview on the extraction of bioactive compounds from Phaleria macrocarpa (Thymelaceae). Nat Prod Chem Res 4: 232.\nAmir H, Murcitro BG, Ahmad AS, Kassim NMI (2010) The potential use of Phaleria macrocarpa leaves extract as an alternative drug for breast cancer among women living in poverty. Asian J Poverty Stud 3(Lmic): 138–145.\nAn M, Fu X, Meng X, Liu H, Ma Y, Li Y, Li Q, Chen J (2024) PI3K/AKT signaling pathway associates with pyroptosis and inflammation in patients with endometriosis. J Reprod Immunol 162: 104213. https://doi.org/10.1016/j.jri.2024.104213\nAndrean D, Prasetyo S, Kristijarti AP, Hudaya T (2014) The extraction and activity test of bioactive compounds in Phaleria macrocarpa as antioxidants. Procedia Chem 9: 94–101. https://doi.org/10.1016/j.proche.2014.05.012\nArsul MI, Setiawansyah A, Insanu M, Fidrianny I (2025) Antihyperuricemia and chemical composition of Boehmeria virgata, in vitro and in silico approach with ADME prediction. Nat Prod Res 1–6: https://doi.org/10.1080/14786419.2025.2471848\nBina F, Soleymani S, Toliat T, Hajimahmoodi M, Tabarrai M, Abdollahi M, Rahimi R (2019) Plant-derived medicines for treatment of endometriosis: A comprehensive review of molecular mechanisms. Pharmacol Res 139: 76–90. https://doi.org/10.1016/j.phrs.2018.11.008\nBitencourt-Ferreira G, de Azevedo WF (2019) Molegro Virtual Docker for Docking. In: de Azevedo Jr. W (ed.). Docking Screens for Drug Discovery. Methods in Molecular Biology, vol 2053. New York, NY: Humana, vol. 2050, pp. 149–167. https://doi.org/10.1007/978-1-4939-9752-7_10\nBosetti C, Santucci C, Gallus S, Martinetti M, La Vecchia C (2020) Aspirin and the risk of colorectal and other digestive tract cancers: An updated meta-analysis through 2019. Ann Oncol 31(5): 558–568. https://doi.org/10.1016/j.annonc.2020.02.012\nCapobianco A, Rovere-Querini P (2013) Endometriosis, a disease of the macrophage. Front Immunol 4(1): 9. https://doi.org/10.3389/fimmu.2013.00009\nChantalat E, Valera-MC, Vaysse C, Noirrit E, Rusidze M, Weyl A, Vergriete K, Buscail E, Lluel P, Fontaine C, Arnal-JF, Lenfant F (2020) Estrogen receptors and endometriosis. Int J Mol Sci 21(8): 2815. https://doi.org/10.3390/ijms21082815\nFerdous UT, Yusof ZNB (2021) Medicinal prospects of antioxidants from algal sources in cancer therapy. Front Pharmacol 12: 593116. https://doi.org/10.3389/fphar.2021.593116\nFuentes N, Silveyra P (2019) Chapter Three - Estrogen receptor signaling mechanisms. Adv Protein Chem Struct Biol 116: 135–170. https://doi.org/10.1016/bs.apcsb.2019.01.001\nGandhi J, Khera L, Gaur N, Paul C, Kaul R (2017) Role of modulator of inflammation cyclooxygenase-2 in gammaherpesvirus mediated tumorigenesis. Front Microbiol 8: 538. https://doi.org/10.3389/fmicb.2017.00538\nGazvani R, Templeton A (2002) Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis. Reproduction 123(2): 217–226. https://doi.org/10.1530/rep.0.1230217\nGoetz GH, Shalaeva M, Caron G, Ermondi G, Philippe L (2017) Relationship between passive permeability and molecular polarity using block relevance analysis. Mol Pharm 14(2): 386–393. https://doi.org/10.1021/acs.molpharmaceut.6b00724\nGreten FR, Grivennikov SI (2019) Inflammation and cancer: Triggers, mechanisms, and consequences. Immunity 51(1): 27–41. https://doi.org/10.1016/j.immuni.2019.06.025\nHakkola J, Hukkanen J, Turpeinen M, Pelkonen O (2020) Inhibition and induction of CYP enzymes in humans: An update. Arch Toxicol 94(11): 3671–3722. https://doi.org/10.1007/s00204-020-02936-7\nHassan IM, Ibrahim WNW, Yusuf FBM, Ahmad SA, Ahmad S (2020) Biochemical constituents of Phaleria macrocarpa (leaf) methanolic extract inhibit ROS production in SH-SY5Y cells model. Biochem Res Int 2020: 2640873. https://doi.org/10.1155/2020/2640873\nHou J, Karin M, Sun B (2021) Targeting cancer-promoting inflammation — have anti-inflammatory therapies come of age? Nat Rev Clin Oncol 18(5): 261–279. https://doi.org/10.1038/s41571-020-00459-9\nHusain F, Siddiqui ZA, Siddiqui M (2015) A case of endometriosis presenting as an inguinal hernia. BMJ Case Rep 2015: bcr2014208099. https://doi.org/10.1136/bcr-2014-208099\nIlhan M, Gürağaç Dereli FT, Akkol EK (2019) Novel drug targets with traditional herbal medicines for overcoming endometriosis. Curr Drug Deliv 16(5): 386–399. https://doi.org/10.2174/1567201816666181227112421\nJiang M, Qi L, Li L, Li Y (2020) The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer. Cell Death Discov 6: 112. https://doi.org/10.1038/s41420-020-00349-0\nKim K (2024) The role of endocrine disruption chemical-regulated aryl hydrocarbon receptor activity in the pathogenesis of pancreatic diseases and cancer. Int J Mol Sci 25(7): 3818. https://doi.org/10.3390/ijms25073818\nKim TH, Yu Y, Luo L, Lydon JP, Jeong JW, Kim JJ (2014) Activated AKT pathway promotes establishment of endometriosis. Endocrinology 155(5): 1921–1930. https://doi.org/10.1210/en.2013-1951\nKong S, Zhang YH, Liu CF, Tsui I, Guo Y, Ai BB, Han FJ (2014) The complementary and alternative medicine for endometriosis: A review of utilization and mechanism. Evid Based Complement Alternat Med 2014: 146383. https://doi.org/10.1155/2014/146383\nKopustinskiene DM, Jakstas V, Savickas A, Bernatoniene J (2020) Flavonoids as anticancer agents. Nutrients 12(2): 457. https://doi.org/10.3390/nu12020457\nLai ZZ, Yang HL, Ha SY, Chang KK, Mei J, Zhou WJ, Qiu XM, Wang XQ, Zhu R, Li DJ, Li MQ (2019) Cyclooxygenase-2 in endometriosis. Int J Biol Sci 15(13): 2783–2797. https://doi.org/10.7150/ijbs.35128\nLay MM, Karsani SA, Banisalam B, Mohajer S, Abd Malek SN (2014) Antioxidants, phytochemicals, and cytotoxicity studies on Phaleria macrocarpa (Scheff.) Boerl Seeds. BioMed Res Int 2014: 410184. https://doi.org/10.1155/2014/410184\nMaddern J, Grundy L, Castro J, Brierley SM (2020) Pain in endometriosis. Front Cell Neurosci 14(1): 590823. https://doi.org/10.3389/fncel.2020.590823\nMaharani 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\nMahnke JL, Yusoff Dawood M, Huang JC (2000) Vascular endothelial growth factor and interleukin-6 in peritoneal fluid of women with endometriosis. Fertil Steril 73(1): 166–170. https://doi.org/10.1016/S0015-0282(99)00466-5\nMalvezzi H, Marengo EB, Podgaec S, Piccinato CDA (2020) Endometriosis: Current challenges in modeling a multifactorial disease of unknown etiology. J Transl Med 18: 311. https://doi.org/10.1186/s12967-020-02471-0\nMao Q, Unadkat JD (2015) Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport—An update. AAPS J 17: 65–82. https://doi.org/10.1208/s12248-014-9668-6\nMeresman GF, Götte M, Laschke MW (2021) Plants as source of new therapies for endometriosis: A review of preclinical and clinical studies. Hum Reprod Update 27(2): 367–392. https://doi.org/10.1093/humupd/dmaa039\nMoga MA, Bălan A, Dimienescu OG, Burtea V, Dragomir RM, Anastasiu CV (2019) Circulating miRNAs as biomarkers for endometriosis and endometriosis-related ovarian cancer— An overview. J Clin Med 8(5): 735. https://doi.org/10.3390/jcm8050735\nMorotti M, Vincent K, Becker CM (2017) Mechanisms of pain in endometriosis. Eur J Obstet Gynecol Reprod Biol 209: 8–13. https://doi.org/10.1016/j.ejogrb.2016.07.497\nNegi RR, Rana SV, Gupta V, Gupta R, Chadha VD, Prasad KK, Dhawan DK (2019) Over-expression of cyclooxygenase-2 in colorectal cancer patients. Asian Pac J Cancer Prev 20(6): 1675–1681. https://doi.org/10.31557/APJCP.2019.20.6.1675\nNephew KP, Long X, Osborne E, Burke KA, Ahluwalia A, Bigsby RM (2000) Effect of estradiol on estrogen receptor expression in rat uterine cell types. Biol Reprod 62(1): 168–177. https://doi.org/10.1095/biolreprod62.1.168\nNisenblat V, Bossuyt PMM, Shaikh R, Farquhar C, Jordan V, Scheffers CS, Mol BWJ, Johnson N, Hull ML (2016) Blood biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev 2016(5): CD012179. https://doi.org/10.1002/14651858.CD012179\nParazzini F, Esposito G, Tozzi L, Noli S, Bianchi S (2017) Epidemiology of endometriosis and its comorbidities. Eur J Obstet Gynecol Reprod Biol 209: 3–7. https://doi.org/10.1016/j.ejogrb.2016.04.021\nPardridge WM (2012) Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab 32(11): 1959–1972. https://doi.org/10.1038/jcbfm.2012.126\nParis A, Tardif N, Galibert MD, Corre S (2021) AhR and cancer: From gene profiling to targeted therapy. Int J Mol Sci 22(2): 752. https://doi.org/10.3390/ijms22020752\nPonder KG, Boise LH (2019) The prodomain of caspase-3 regulates its own removal and caspase activation. Cell Death Discov 5: 56. https://doi.org/10.1038/s41420-019-0142-1\nReis FM, Coutinho LM, Vannuccini S, Batteux F, Chapron C, Petraglia F (2020) Progesterone receptor ligands for the treatment of endometriosis: The mechanisms behind therapeutic success and failure. Hum Reprod Update 26(4): 565–585. https://doi.org/10.1093/humupd/dmaa009\nRocha AL, Reis FM, Taylor RN (2012) Angiogenesis and endometriosis. Obstet Gynecol Int 2013: 859619. https://doi.org/10.1155/2013/859619\nSahraei SS, Davoodi Asl F, Kalhor N, Sheykhhasan M, Fazaeli H, Moud SS, Sheikholeslami A (2022) A comparative study of gene expression in menstrual blood-derived stromal cells between endometriosis and healthy women. BioMed Res Int 2022: 7053521. https://doi.org/10.1155/2022/7053521\nSari DRT, Krisnamurti GC, Bare Y (2022) Virtual mapping of secondary metabolite activities containing in Caesalpinia sappan L. heartwood through in silico study. J Pharm Sci 7(1): 21–28. https://doi.org/10.53342/pharmasci.v7i1.274\nSatoh H, Amagase K, Ebara S, Akiba Y, Takeuchi K (2013) Cyclooxygenase (COX)-1 and COX-2 both play an important role in the protection of the duodenal mucosa in cats. J Pharmacol Exp Ther 344(1): 189–195. https://doi.org/10.1124/jpet.112.199182\nSingh K, Bhori M, Kasu YA, Bhat G, Marar T (2018) Antioxidants as precision weapons in war against cancer chemotherapy induced toxicity – Exploring the armoury of obscurity. Saudi Pharm J 26(2): 177–190. https://doi.org/10.1016/j.jsps.2017.12.013\nSmolarz B, Szyłło K, Romanowicz H (2021) Endometriosis: Epidemiology, classification, pathogenesis, treatment and genetics (review of literature). Int J Mol Sci 22(19): 10554. https://doi.org/10.3390/ijms221910554\nSrinivas US, Tan BWQ, Vellayappan BA, Jeyasekharan AD (2019) ROS and the DNA damage response in cancer. Redox Biol 25: 101084. https://doi.org/10.1016/j.redox.2018.101084\nSutrisno S, Andarini S, Wiyasa IWA, Kulsum U, Noerhamdani N, Suyuti H, Hendarto H (2019) The Effect of implant origin differences on peritoneal endometriosis in an endometriosis mouse model. Int J Women's Health Reprod Sci 7(1): 34–40. https://doi.org/10.15296/ijwhr.2019.06\nSzweda M, Rychlik A, Babińska I, Pomianowski A (2019) Significance of cyclooxygenase-2 in oncogenesis. J Vet Res 63(2): 215–224. https://doi.org/10.2478/jvetres-2019-0030\nTandrasasmita OM, Sutanto AM, Arifin PF, Tjandrawinata RR (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 7: 161–169. https://doi.org/10.2147/ijwh.s74552\nTsai PJ, Lin YH, Chen JL, Yang SH, Chen YC, Chen HY (2017) Identifying Chinese herbal medicine network for endometriosis: Implications from a population-based database in Taiwan. Evid Based Complement Alternat Med 2017: 7501015. https://doi.org/0.1155/2017/7501015\nTsuji N, Fukuda K, Nagata Y, Okada H, Haga A, Hatakeyama S, Yoshida S, Okamoto T, Hosaka M, Sekine K, Ohtaka K, Yamamoto S, Otaka M, Grave E, Itoh H (2014) The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90. FEBS Open Bio 4(1): 796–803. https://doi.org/10.1016/j.fob.2014.09.003\nVallvé-Juanico J, Houshdaran S, Giudice LC (2019) The endometrial immune environment of women with endometriosis. Hum Reprod Update 25(5): 565–592. https://doi.org/10.1093/humupd/dmz018\nVara JÁF, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30(2): 193–204. https://doi.org/10.1016/j.ctrv.2003.07.007\nWang Z, Snyder M, Kenison JE, Yang K, Lara B, Lydell E, Bennani K, Novikov O, Federico A, Monti S, Sherr DH (2021) How the AHR became important in cancer: The role of chronically active AHR in cancer aggression. Int J Mol Sci 22(1): 387. https://doi.org/10.3390/ijms22010387\nYin W, Xiang D, Wang T, Zhang Y, Pham CV, Zhou S, Jiang G, Hou Y, Zhu Y, Han Y, Qiao L, Tran PHL, Duan W (2021) The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cells. Sci Rep 11: 10791. https://doi.org/10.1038/s41598-021-89931-9\nZheng W, Wu J, Gu J, Weng H, Wang J, Wang T, Liang X, Cao L (2020) Modular characteristics and mechanism of action of herbs for endometriosis treatment in Chinese medicine: A data mining and network pharmacology–based identification. Front Pharmacol 11(1): 147. https://doi.org/10.3389/fphar.2020.00147\n© 2026 Journal of Pharmacy & Pharmacognosy Research","source_license":"CC0","license_restricted":false}