title: Discovery of Novel Selective ERα/ERβ Ligands by Multi-pharmacophore Modeling and Virtual Screening.
abstract: Estrogen receptor α (ERα) and estrogen receptor β (ERβ) regulate different sets of gene expression, and have different ligand responses, which make the estrogen tissue-specific. Thus, the estrogen receptor (ER) subtype-selective ligands can improve the target-site selectivity and decrease the off-target effect. In order to discover the selective ER subtype ligands with novel scaffolds, in this work three-dimensional (3D) pharmacophore models of the ERα ligands (Hypo 1) and the ERβ ligands (Hypo 2) were established (correlation coefficients were 0.959 and 0.966) and validated (R=0.936 and 0.879; enrichment factors (EFs) at 2% were 16.2 and 8.4; areas under the concentration-time curve (AUC) of the receiver operating curve (ROC) were 0.88 and 0.91) using the Discovery Studio 4.0 software package. Hypo 1 and Hypo 2 were then employed for virtual screening and ten hits were found as potential candidate leads. Based on their ERα/ERβ binding affinity results by fluorescence polarization technology, two of these leads, AH-262/34334025 (AH) and AG-670/08803023 (AG) with novel scaffolds were identified as selective ERα ligands. A molecular docking study was also performed, which provided the explanation for the ER subtype preferences for AH and AG.
authors.affiliation: Institute of Materia Medica, Zhejiang Academy of Medical Sciences.
authors.forename: Wenhai
authors.initials: W
authors.lastname: Huang
authors.forename: Wenhua
authors.initials: W
authors.lastname: Wei
authors.forename: Yewei
authors.initials: Y
authors.lastname: Yang
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Shen
mesh_terms: D062313:Databases, Pharmaceutical; D055808:Drug Discovery; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D054852:Small Molecule Libraries