A Loop‐Based and AGO‐Incorporated Virtual Screening Model Targeting AGO‐Mediated miRNA–mRNA Interactions for Drug Discovery to Rescue Bone Phenotype in Genetically Modified Mice. Issue 13 (28th May 2020)

• Record Type: Journal Article
• Authors: Zhuo, Zhenjian; Wan, Youyang; Guan, Daogang; Ni, Shuaijian; Wang, Luyao; Zhang, Zongkang; Liu, Jin; Liang, Chao; Yu, Yuanyuan; Lu, Aiping; Zhang, Ge; Zhang, Bao‐Ting
• Is Part Of: Advanced science. Volume 7:Issue 13(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-05-28
• Subjects: bone rescue -- drug discovery -- miRNA–mRNA interactions -- small molecule screening -- virtual screening models; Science -- Periodicals; 505
• DOI: 10.1002/advs.201903451
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: 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. Abstract : It is found that mature miRNA and their specific target mRNA can form unique functional loops during argonaute (AGO)‐mediated miRNA–mRNA interactions. Thus, a loop‐based and AGO‐incorporated virtual screening model is constructed for screening small molecules targeting the loops. By using the virtual model, two small molecules are obtained that can specifically target miR‐214‐ATF4 mRNA interactions and miR‐214‐TRAF3 mRNA interactions, respectively.