Discovery of Novel Selective ER alpha/ER beta Ligands by Multi-pharmacophore Modeling and Virtual Screening

作者：Huang Wenhai; Wei Wenhua; Yang Yewei; Zhang Tao; Shen Zhengrong^*

来源：Chemical & Pharmaceutical Bulletin, 2015, 63(10): 780-791.

DOI：10.1248/cpb.c15-00256

• estrogen receptor ligand
• pharmacophore model
• virtual screening

Estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) 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 A ligands (Hypo 1) and the ER beta 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 ER alpha/ER beta 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 ER alpha ligands. A molecular docking study was also performed, which provided the explanation for the ER subtype preferences for All and AG.

• 出版日期2015-10
• 单位浙江省医学科学院