Human Estrogen Receptor α Antagonists. Part 1: 3-D QSAR-Driven Rational Design of Innovative Coumarin-Related Antiestrogens as Breast Cancer Suppressants through Structure-Based and Ligand-Based Studies,Journal of Chemical Information and Modeling

当前位置： X-MOL 学术 › J. Chem. Inf. Model. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Human Estrogen Receptor α Antagonists. Part 1: 3-D QSAR-Driven Rational Design of Innovative Coumarin-Related Antiestrogens as Breast Cancer Suppressants through Structure-Based and Ligand-Based Studies
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2021-10-14 , DOI: 10.1021/acs.jcim.1c00530
Nezrina Mihović ₁ , Nevena Tomašević ₁ , Sanja Matić ₂ , Marina M Mitrović ₃ , Danijela A Kostić ₄ , Manuela Sabatino ₅ , Lorenzo Antonini ₅ , Rino Ragno ₅ , Milan Mladenović ₁

Affiliation

The estrogen receptor α (ERα) represents a 17β-estradiol-inducible transcriptional regulator that initiates the RNA polymerase II-dependent transcriptional machinery, pointed for breast cancer (BC) development via either genomic direct or genomic indirect (i.e., tethered) pathway. To develop innovative ligands, structure-based (SB) three-dimensional (3-D) quantitative structure–activity relationship (QSAR) studies have been undertaken from structural data taken from partial agonists, mixed agonists/antagonists (selective estrogen receptor modulators (SERMs)), and full antagonists (selective ERα downregulators (SERDs)) correlated with either wild-type or mutated ERα receptors. SB and ligand-based (LB) alignments allow us to rule out guidelines for the SB/LB alignment of untested compounds. 3-D QSAR models for ERα ligands, coupled with SB/LB alignment, were revealed to be useful tools to dissect the chemical determinants for ERα-based anticancer activity as well as to predict their potency. The herein developed protocol procedure was verified through the design and potency prediction of 12 new coumarin-based SERMs, namely, 3DQ-1a to 3DQ-1e, that upon synthesis turned to be potent ERα antagonists by means of either in vitro or in vivo assays (described in the second part of this study).

中文翻译：

人雌激素受体α拮抗剂。第 1 部分：通过基于结构和基于配体的研究，3-D QSAR 驱动的创新香豆素相关抗雌激素作为乳腺癌抑制剂的合理设计

雌激素受体 α (ERα) 代表 17β-雌二醇诱导的转录调节因子，它启动依赖于 RNA 聚合酶 II 的转录机制，通过基因组直接或基因组间接指向乳腺癌 (BC) 发展（即., 系留）路径。为了开发创新的配体，基于结构 (SB) 的三维 (3-D) 定量构效关系 (QSAR) 研究已经从部分激动剂、混合激动剂/拮抗剂（选择性雌激素受体调节剂 (SERM) ))，以及与野生型或突变型 ERα 受体相关的完全拮抗剂（选择性 ERα 下调剂 (SERD)）。SB 和基于配体 (LB) 的比对允许我们排除未测试化合物的 SB/LB 比对指南。ERα 配体的 3-D QSAR 模型与 SB/LB 比对相结合，被证明是剖析基于 ERα 的抗癌活性的化学决定因素以及预测其效力的有用工具。3DQ-1a到3DQ-1e，通过体外或体内试验（在本研究的第二部分中描述），合成后变成有效的 ERα 拮抗剂。

更新日期：2021-10-25

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11