Tumor dissemination and relapse in lung cancer were found to be due to the existence of cancer stem cells. In particular, the [Formula: see text]-catenin pathway is found to be one of the crucial pathways in maintaining the stem-like properties of the cells. Thus, targeting the [Formula: see text]-catenin family of proteins is a significant therapeutic route in the treatment of lung cancer. Therefore, in the present study, a pharmacophore-based drug repurposing approach was accomplished to pinpoint potent [Formula: see text]-catenin inhibitors from the DrugBank database. Primarily, ligand-based pharmacophore hypothesis (AAHHR) was generated using existing [Formula: see text]-catenin inhibitors available in the literature and utilized for library screening. Subsequently, the inhibitory activity of the screened compounds was examined by the hierarchical docking process and the Prime MM-GBSA algorithm. Moreover, quantum chemical calculations and molecular dynamics simulations were executed to analyze the inhibitory effects of the screened hit molecule. The results indicate that hit molecule, DB08047 was found to possess better binding free energy, favorable ligand strain energy, satisfactory pharmacokinetic properties and superior free energy landscape profile. Eventually, the pIC[Formula: see text] values of the lead compounds were predicted by the AutoQSAR algorithm. It is noteworthy to mention that DB08047 was found to possess pyrazole scaffolds which could downregulate [Formula: see text]-catenin pathway and thus facilitate the controlled cell growth/inhibit tumor growth.

中文翻译：

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发现β-连环蛋白选择性抑制剂的分子模拟策略

肺癌的肿瘤扩散和复发被发现是由于癌症干细胞的存在。特别是，[公式：见正文]-连环蛋白途径被发现是维持细胞干细胞样特性的关键途径之一。因此，靶向[公式：见正文]-连环蛋白家族是治疗肺癌的重要治疗途径。因此，在本研究中，完成了一种基于药效团的药物再利用方法，以从 DrugBank 数据库中查明有效的 [公式：见正文]-连环蛋白抑制剂。首先，基于配体的药效团假说 (AAHHR) 是使用文献中现有的 [公式：见正文]-连环蛋白抑制剂生成的，并用于文库筛选。随后，通过分级对接过程和 Prime MM-GBSA 算法检查筛选化合物的抑制活性。此外，还进行了量子化学计算和分子动力学模拟，以分析筛选出的命中分子的抑制作用。结果表明，命中分子 DB08047 被发现具有更好的结合自由能、有利的配体应变能、令人满意的药代动力学性质和优越的自由能分布图。最终，通过 AutoQSAR 算法预测了先导化合物的 pIC[公式：见正文] 值。值得注意的是，DB08047被发现具有吡唑支架，可以下调[公式：见正文]-连环蛋白途径，从而促进受控细胞生长/抑制肿瘤生长。