Several virtual screening models are proposed to screen small molecules only targeting primary miRNAs without selectivity. Few attempts have been made to develop virtual screening strategies for discovering small molecules targeting mature miRNAs. Mature miRNAs and their specific target mRNA can form unique functional loops during argonaute (AGO)‐mediated miRNA–mRNA interactions, which may serve as potential targets for small‐molecule drug discovery. Thus, a loop‐based and AGO‐incorporated virtual screening model is constructed for targeting the loops. The previously published studies have found that miR‐214 can target ATF4 to inhibit osteoblastic bone formation, whereas miR‐214 can target TRAF3 to promote osteoclast activity. By using the virtual model, the top ten candidate small molecules targeting miR‐214‐ATF4 mRNA interactions and top ten candidate small molecules targeting miR‐214‐TRAF3 mRNA interactions are selected, respectively. Based on both in vitro and in vivo data, one small molecule can target miR‐214‐ATF4 mRNA to promote ATF4 protein expression and enhance osteogenic potential, whereas one small molecule can target miR‐214‐TRAF3 mRNA to promote TRAF3 protein expression and inhibit osteoclast activity. These data indicate that the loop‐based and AGO‐incorporated virtual screening model can help to obtain small molecules specifically targeting miRNA–mRNA interactions to rescue bone phenotype in genetically modified mice.

中文翻译：

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基于环和基于AGO的虚拟筛选模型，该模型针对AGO介导的miRNA-mRNA相互作用，用于药物发现以挽救转基因小鼠的骨表型。

提出了几种虚拟筛选模型来筛选仅靶向初级miRNA的小分子而没有选择性。很少尝试开发虚拟筛选策略来发现靶向成熟miRNA的小分子。成熟的miRNA及其特异的靶mRNA可以在精子（AGO）介导的miRNA-mRNA相互作用过程中形成独特的功能环，这可能成为小分子药物发现的潜在靶标。因此，构建了一个以循环为基础并结合AGO的虚拟筛选模型，以针对循环。先前发表的研究发现，miR-214可以靶向ATF4抑制成骨细胞的骨形成，而miR-214可以靶向TRAF3促进破骨细胞的活性。通过使用虚拟模型，分别选择了靶向miR-214-ATF4 mRNA相互作用的十大候选小分子和靶向miR-214-TRAF3 mRNA相互作用的十大候选小分子。根据体内和体外数据，一个小分子可以靶向miR‐214‐ATF4 mRNA来促进ATF4蛋白表达并增强成骨潜能，而一个小分子可以靶向miR‐214‐TRAF3 mRNA来促进TRAF3蛋白表达并抑制破骨细胞活性。这些数据表明，基于环和AGO的虚拟筛选模型可以帮助获得专门针对miRNA-mRNA相互作用的小分子，以挽救转基因小鼠的骨表型。一个小分子可以靶向miR‐214‐ATF4 mRNA来促进ATF4蛋白表达并增强成骨潜能，而一个小分子可以靶向miR‐214‐TRAF3 mRNA来促进TRAF3蛋白表达并抑制破骨细胞活性。这些数据表明，基于环和AGO的虚拟筛选模型可以帮助获得专门针对miRNA-mRNA相互作用的小分子，以挽救转基因小鼠的骨表型。一个小分子可以靶向miR‐214‐ATF4 mRNA来促进ATF4蛋白表达并增强成骨潜能，而一个小分子可以靶向miR‐214‐TRAF3 mRNA来促进TRAF3蛋白表达并抑制破骨细胞活性。这些数据表明，基于环和AGO的虚拟筛选模型可以帮助获得专门针对miRNA-mRNA相互作用的小分子，以挽救转基因小鼠的骨表型。