Structure-based quantitative structure–activity relationship modeling of estrogen receptor β-ligands

Abstract

Background: A variety of chemotypes have been studied as estrogen receptor (ER) β-selective ligands for potential drugs against various indications, including neurodegenerative diseases. Their structure–activity relationship data and the x-ray structures of the ERβ ligand-binding domain bound with different ligands have become available. Thus, it is vitally important for future development of ERβ-selective ligands that robust quantitative structure–activity relationship (QSAR) models be built. Methods/results: We employed a newly developed structure-based QSAR method (structure-based pharmacophore keys QSAR) that utilizes both the structure–activity relationship data and the 3D structural information of ERβ, as well as a robust QSAR workflow to analyze 37 ligands. Four sets of QSAR models were obtained, among which approximately 30 models afforded high (>0.60) training-r2 and test set-R2 statistics. Conclusion: We have obtained an ensemble of predictive models of ERβ ligands that will be useful in the future discovery of novel ERβ-selective molecules.