QSAR study of natural estrogen-like isoflavonoids and diphenolics from Thai medicinal plants

Two species of Thai medicinal plants, Dalbergia parviflora R. (Leguminosae) and Belamcanda chinensis L. (Iridaceae), used traditionally for the regulation of menstrual disorders, have been found to contain a large number of potential estrogen-like compounds. A set of some 55 isolated isoflavonoids and diphenolics showed a wide range of estrogen activity as determined in breast cancer MCF-7 and T47D cell proliferation assays. This set of compounds was studied by means of computational techniques including quantitative structure–activity relationships (QSAR) and molecular modeling. It was found that the estrogenic potencies of the studied compounds depend mainly upon the presence/absence of hydroxyl groups attached to 3′ and 5′ positions of B ring of the isoflavone scaffold and the inter-atomic distance between the hydroxyl groups attached to the outer terminal positions 7 of A ring and 4′ of B ring. In a QSAR model employing ligand–receptor interaction energy descriptors, the LigScore scoring function of Cerius2 virtual screening module, which describes the receptor affinities of simultaneous binding to estrogenic receptors α and β (ERα and ERβ), led to the best correlation between the observed estrogenic activities and computed descriptors. Consideration of independent binding to ERα and ERβ did not result in statistically significant QSAR models. It was thus concluded that simultaneous and possibly competitive interaction of the compounds with the ERα and ERβ receptors, in which the presence of hydroxyl groups at the abovementioned positions of the isoflavonoids and diphenolics molecular scaffold plays a dominant role, may determine the estrogenic potency of the considered phytochemicals.

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► The LigScore scoring function led to the best correlation between the observed biological activities and computed descriptors representing binding affinity to estrogenic receptors α (ERα) and β (ERβ).
► The QSAR analyses showed that the presence of hydroxyl or methoxy groups at the C6 and C14 positions in the superposed structural scheme is essential for the observed estrogenic activity.
► Substitutions in ortho and meta positions of the benzene ring of isoflavonoid scaffold decrease the estrogenic activity.
► Simultaneous and possibly competitive interaction of the compounds with the ERα and ERβ receptors play a dominant role in the estrogenic potency of the studied series of phytochemicals.