5-O-Methylgenistein of Phaleria macrocarpa (Scheff.) Boerl. revealed as a potential therapeutic compound for endometriosis

Context: 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. Aims: To predict biological activities of selected P. macrocarpa flavonoids and to explore potential protein–ligand interactions with endometriosis-relevant targets using molecular docking.

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.

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).

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.

AKT; cyclooxygenase-2; endometriosis; molecular docking; Phaleria macrocarpa; phytoestrogens. Resumen Contexto: 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. Objetivos: Predecir las actividades biológicas de flavonoides seleccionados de P. macrocarpa y explorar posibles interacciones proteína-ligando relevantes para la endometriosis mediante acoplamiento molecular. Métodos: 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. Resultados: 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). Conclusiones: 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. Palabras Clave: acoplamiento molecular; AKT; ciclooxigenasa-2; endometriosis; fitoestrógenos; Phaleria macrocarpa. Citation 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

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