文献类型：期刊文献

英文题名：Computational Insights into Ligand Selectivity of Estrogen Receptors from Pharmacophore Modeling

作者：Fang, Jing[1];Shen, Jie[1];Cheng, Feixiong[1];Xu, Zhejun[1];Liu, Guixia[1];Tang, Yun[1]

机构：[1]E China Univ Sci & Technol, Dept Pharmaceut Sci, Sch Pharm, Shanghai 200237, Peoples R China

年份：2011

卷号：30

期号：6-7

起止页码：539

外文期刊名：MOLECULAR INFORMATICS

收录：;EI(收录号：20232414244029);WOS:【SCI-EXPANDED(收录号:WOS:000293847700005)】；

基金：This work was supported by the National Natural Science Foundation of China (Grant No. 21072059), the Program for New Century Excellent Talents in University (Grant No. NCET-08-0774), the 111 Project (Grant No. B07023), and the National S&T Major Project of China (Grant No. 2009ZX09501-001).

语种：英文

外文关键词：Estrogen receptor; Ligand selectivity; Molecular modeling; Pharmacophore

摘要：Estrogen receptors (ERs) belong to the nuclear receptor superfamily, which play crucial roles in the human body. To date, two subtypes, ER alpha and ER beta, have been identified. The function and expression of both subtypes are various, stimulating the interest for discovering subtype selective ligands. However, ER alpha and ER beta are highly homologous. They share 56% sequence identity in the ligand binding domain and only two pairs of residues differ in the ligand binding pocket. In this study, pharmacophore models were built for both subtypes based on 23 ER alpha and 24 ER beta selective ligands, respectively. It was found from these pharmacophore models that hydrophobic and hydrogen bonding interactions were essential for the subtype selectivity. The hydrogen bond donor feature in the phenol part was a favorable contribution to ER beta selectivity, whereas the one in the benzopyran part of the ligand was important for ER alpha selectivity. Furthermore, simulated virtual screening was performed with both subtype specific pharmacophore models. The results confirmed the reliability and discrimination ability of both models. These findings could not only be helpful for the understanding of a possible mechanism underlying ligand selectivity of ERs, but could also pave a new avenue for the discovery of novel selective ER ligands.