University of Louisville

Poster Title

Quantitative Structure-Activity Relationships of the Molecular Diversity of the Estrogen Response Mechanism by Human Estrogen Receptor-alpha (hERα)

Presenter Information

Huy Le, University of Louisville

Institution

University of Louisville

Abstract

Diverse chemical features of estrogens and their mimics are illustrated by the promiscuous nature of their interactions with the ligand binding domain (LBD) of the human estrogen receptor alpha (hERα). In order to better understand structure characteristics of interactions between ligand and LBD, the biological activities of ligands are modeled using alignment software DISCOtechT. Pharmacophores generated are also subjected to Comparative Molecular Field Analysis and Partial Least Square Analysis to determine quantitatively the relationship between three-dimensional ligand structures and corresponding activities. The dataset utilized consisted of biological activities of 25 compounds from extensive titration arrays performed with yeast-derived recombinant hERα. Collectively, these mimics competed with estradiol-17β over a broad spectrum of relative binding affinities ranging from 0-150%. Six initial models were generated illustrating binding affinities of mimics at different levels of receptor occupancy. A seventh model was generated to look at the average affinity of mimics for hERα. The models displayed good predictive ability (q2 > 0.6). When the average of the first six models were compared to the values calculated from seventh model, these two datasets displayed strong correlation (r2 = 0.75) indicating internal consistency. Future studies will incorporate extensive data from other experiments such as Electrophoretic Mobility Shift Assay and cell-based bioassays. A broad range of ligand binding affinities from chemically diverse molecules, biological data and enhanced three-dimensional structures for the LBD will provide a comprehensive model of ligand-receptor interactions of hERα.

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Quantitative Structure-Activity Relationships of the Molecular Diversity of the Estrogen Response Mechanism by Human Estrogen Receptor-alpha (hERα)

Diverse chemical features of estrogens and their mimics are illustrated by the promiscuous nature of their interactions with the ligand binding domain (LBD) of the human estrogen receptor alpha (hERα). In order to better understand structure characteristics of interactions between ligand and LBD, the biological activities of ligands are modeled using alignment software DISCOtechT. Pharmacophores generated are also subjected to Comparative Molecular Field Analysis and Partial Least Square Analysis to determine quantitatively the relationship between three-dimensional ligand structures and corresponding activities. The dataset utilized consisted of biological activities of 25 compounds from extensive titration arrays performed with yeast-derived recombinant hERα. Collectively, these mimics competed with estradiol-17β over a broad spectrum of relative binding affinities ranging from 0-150%. Six initial models were generated illustrating binding affinities of mimics at different levels of receptor occupancy. A seventh model was generated to look at the average affinity of mimics for hERα. The models displayed good predictive ability (q2 > 0.6). When the average of the first six models were compared to the values calculated from seventh model, these two datasets displayed strong correlation (r2 = 0.75) indicating internal consistency. Future studies will incorporate extensive data from other experiments such as Electrophoretic Mobility Shift Assay and cell-based bioassays. A broad range of ligand binding affinities from chemically diverse molecules, biological data and enhanced three-dimensional structures for the LBD will provide a comprehensive model of ligand-receptor interactions of hERα.