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Development of structure-based pharmacophore to target the β-catenin-TCF protein–protein interaction
Medicinal Chemistry Research ( IF 2.6 ) Pub Date : 2021-01-12 , DOI: 10.1007/s00044-020-02693-3
Piyusha P. Pagare , Andrew Morris , Jiong Li , Yan Zhang

β-catenin concentration is methodically controlled by the Wnt signaling pathway, wherein mutations of this pathway can cause aberrant activation leading to an influx of β-catenin, which is implicated in many cancers, specifically colon cancer. Targeting the β-catenin-TCF interface has become a popular strategy because of its role in the Wnt signaling transduction pathway, but efforts to push a small-molecule inhibitor to clinical success have been futile. In our current study, we attempted to identify druggable “hot spots” at the β-catenin-TCF interface by exploring plausible binding modes of a number of reported and chemically distinct inhibitors and defined their structure-based pharmacophore. Validation of our 4-feature pharmacophore hypothesis was carried out using another series of structure-related inhibitors with reported experimental data. Our hypothesis identified 73% of true actives with high enrichment of the most potent molecules in the test dataset. We speculate that our structure-based pharmacophore query may act as an in silico tool to rapidly screen small-molecule libraries for potentially new scaffolds to disrupt the β-catenin-TCF protein–protein interaction. In addition, our pharmacophore successfully identified actives from a set of structurally similar inhibitors and, ultimately, may be applied as an adjunct tool in the hit-to-lead optimization process.



中文翻译:

针对β-catenin-TCF蛋白质-蛋白质相互作用的基于结构的药效团的开发

β-catenin的浓度受到Wnt信号通路的系统控制,其中该通路的突变可引起异常激活,导致β-catenin大量涌入,这与许多癌症(尤其是结肠癌)有关。由于靶向β-catenin-TCF接口在Wnt信号转导途径中的作用,它已成为一种流行的策略,但是将小分子抑制剂推向临床成功的努力是徒劳的。在我们当前的研究中,我们试图通过探索许多报道的和化学上不同的抑制剂的合理结合模式,并确定其基于结构的药效团,来确定β-catenin-TCF界面上的可药物“热点”。我们的四功能药效基团假说的验证是使用另一组与结构相关的抑制剂进行的,并已报道了实验数据。我们的假设确定了测试数据集中73%的真正活性物质具有最有效分子的高度富集。我们推测,基于结构的药效团查询可能充当计算机软件,可以快速筛选小分子文库中潜在的新支架,以破坏β-catenin-TCF蛋白质与蛋白质的相互作用。此外,我们的药效基团已成功从一组结构相似的抑制剂中鉴定出了活性成分,最终可以用作潜在客户优化过程中的辅助工具。我们推测,基于结构的药效团查询可能充当计算机软件,可以快速筛选小分子文库中潜在的新支架,以破坏β-catenin-TCF蛋白质与蛋白质的相互作用。此外,我们的药效基团已成功从一组结构相似的抑制剂中鉴定出了活性成分,最终可以用作潜在客户优化过程中的辅助工具。我们推测,基于结构的药效团查询可能充当计算机软件,可以快速筛选小分子文库中潜在的新支架,以破坏β-catenin-TCF蛋白质与蛋白质的相互作用。此外,我们的药效基团已成功从一组结构相似的抑制剂中鉴定出了活性成分,最终可以用作潜在客户优化过程中的辅助工具。

更新日期:2021-01-12
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