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. Methods: 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. Results: 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). Conclusions: 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.