ABSTRACT
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 Cerius(2) virtual screening module, which describes the receptor affinities of simultaneous binding to estrogenic receptors α and ß (ER(α) and ER(ß)), led to the best correlation between the observed estrogenic activities and computed descriptors. Consideration of independent binding to ER(α) and ER(ß) did not result in statistically significant QSAR models. It was thus concluded that simultaneous and possibly competitive interaction of the compounds with the ER(α) and ER(ß) 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.
Subject(s)
Biphenyl Compounds/chemistry , Dalbergia/chemistry , Flavonoids/chemistry , Iridaceae/chemistry , Isoflavones/chemistry , Phytoestrogens/chemistry , Plants, Medicinal/chemistry , Quantitative Structure-Activity Relationship , Biphenyl Compounds/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Flavonoids/metabolism , Humans , Hydroxyl Radical/chemistry , Hydroxyl Radical/pharmacology , Isoflavones/metabolism , Models, Molecular , Phytoestrogens/metabolism , Phytoestrogens/pharmacology , Plant Extracts/chemistry , Plant Extracts/metabolism , Receptors, Estrogen/chemistry , Receptors, Estrogen/metabolism , ThailandABSTRACT
Three-dimensional models of exoinulinase from Bacillus stearothermophilus and endoinulinase from Aspergillus niger were built up by means of homology modeling. The crystal structure of exoinulinase from Aspergillus awamori was used as a template, which is the sole structure of inulinase resolved so far. Docking and molecular dynamics simulations were performed to investigate the differences between the two inulinases in terms of substrate selectivity. The analysis of the structural differences between the two inulinases provided the basis for the explanation of their different regio-selectivity and for the understanding of enzyme-substrate interactions. Surface analysis was performed to point out structural features that can affect the efficiency of enzymes also after immobilization. The computational analysis of the three-dimensional models proved to be an effective tool for acquiring information and allowed to formulate an optimal immobilized biocatalyst even more active that the native one, thus enabling the full exploitation of the catalytic potential of these enzymes.
