Molecular docking of flavonoids from Phaleria macrocarpa on the NF-kB p65, VEGFR2, Ki67, COX-2, and CXCR4 pathways in endometriosis

Context: Endometriosis is a condition marked by the presence of endometrial epithelium and stromal cells outside the uterus. Previous studies have shown that prostaglandin E2 has a role in the development of endometriosis via the action of local estrogen and estrogen receptors. Aims: To analyze the molecular docking between Phaleria macrocarpa flavonoid compounds in the NF-kB, VEGF/VEGFR2, Ki67, COX-2, and CXCR4 pathways that are involved in the pathomechanism of endometriosis.

Functional determination of Phaleria macrocarpa phytochemistry using PASS prediction ADMETSAR's prediction of Phaleria macrocarpa's flavonoids compounds meet the Lipinski rule criteria so that they are predicted to have drug-likeness and no toxicity. Phaleria macrocarpa flavonoids were synthesized using AutoDock Tools 1.5.7 software. AutoDock Vina v1.2.3 software was used to perform docking simulations of ligands and target proteins. The results of the docking analysis were visualized with the Discovery Studio 4.1 application.

For the NF-kB pathway, the compounds that showed the highest affinity for interaction to occur were (±)-naringenin (target of NF-kB p50/p65) and (-)-8-prenylnaringenin (the ATP-binding site in IKK). Against VEGF-A and VEGFR2, the flavonoids that exhibited the highest interaction affinity were glycitin, and (-)-8-prenylnaringenin, respectively. The compound that interacted most easily with Ki67, COX-2, or CXCR4 was (+)-catechin 7-O-beta-D-xyloside. For docking with standard drugs, we found that leuprolide acetate and dienogest showed higher affinity for NF-kB p50/p65 heterodimer than flavonoids.

The six compounds Phaleria macrocarpa have different affinities for selected pathways in endometriosis. Thus, the Phaleria macrocarpa flavonoids could be a multi-action herbal candidate for endometriosis, which can be used alone or as a complement to standard drugs.

angiogenesis; endometriosis; inflammation; pathomechanisms; proliferation. Resumen Contexto: La endometriosis es una enfermedad caracterizada por la presencia de epitelio endometrial y células del estroma fuera del útero. Estudios previos han demostrado que la prostaglandina E2 tiene un papel en el desarrollo de la endometriosis a través de la acción de los receptores de estrógenos y estrógenos locales. Objetivos: Analizar el acoplamiento molecular entre los flavonoides de Phaleria macrocarpa en las vías NF-kB, VEGF/VEGFR2, Ki67, COX-2 y CXCR4 que están involucradas en el patomecanismo de la endometriosis. Métodos: Determinación funcional de la fitoquímica de P. macrocarpa mediante predicción PASS La predicción de ADMETSAR de los flavonoides de P. macrocarpa cumple con los criterios de la regla de Lipinski, por lo que se predice que tienen similitud con los fármacos y no son tóxicos. Los flavonoides de P. macrocarpa se sintetizaron utilizando el software AutoDock Tools 1.5.7. Se utilizó el software AutoDock Vina v1.2.3 para realizar simulaciones de acoplamiento de ligandos y proteínas diana. Los resultados del análisis de acoplamiento se visualizaron con la aplicación Discovery Studio 4.1. Resultados: Para la vía NF-kB, los compuestos que mostraron la mayor afinidad para que se produjera la interacción fueron la (±)-naringenina (diana de NF-kB p50/p65) y la (-)-8-prenilnaringenina (el sitio de unión de ATP en IKK). Frente a VEGF-A y VEGFR2, los flavonoides que exhibieron la mayor afinidad de interacción fueron la glicitina y la (-)-8-prenilnaringenina, respectivamente. El compuesto que interactuó más fácilmente con Ki67, COX-2 o CXCR4 fue la (+)-catequina 7-O-beta-D-xilósido. En el caso de la combinación con fármacos estándar, hemos descubierto que el acetato de leuprolida y el dienogest muestran una mayor afinidad por el heterodímero p50/p65 del NF-kB que los fitoquímicos. Conclusiones: Los seis compuestos de P. macrocarpa tienen diferentes afinidades por vías seleccionadas en la endometriosis. Por lo tanto, los flavonoides de P. macrocarpa podrían ser un candidato herbal de acción múltiple para la endometriosis, que puede utilizarse solo o como complemento de los fármacos estándar. Palabras Clave: angiogénesis; endometriosis; inflamación; patomecanismos; proliferación. Citation Format: Maharani M, Sutrisno S, Wiyasa IWA, Endharti AT, Winarsih S, Soeharto S, Indrawan IWA (2025) Molecular docking of flavonoids from Phaleria macrocarpa on the NF-kB p65, VEGFR2, Ki67, COX-2, and CXCR4 pathways in endometriosis. J Pharm Pharmacogn Res 13(2): 527–537. https://doi.org/10.56499/jppres24.2090_13.2.527

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