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

Zhenjian Zhuo, Youyang Wan, Daogang GUAN, Shuaijian Ni, Luyao Wang, Zongkang Zhang, Jin LIU, Chao LIANG, Yuanyuan YU, Aiping LYU, Ge ZHANG, Bao Ting Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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.

Original languageEnglish
Article number1903451
JournalAdvanced Science
Volume7
Issue number13
DOIs
Publication statusPublished - 1 Jul 2020

Scopus Subject Areas

  • Medicine (miscellaneous)
  • Chemical Engineering(all)
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

User-Defined Keywords

  • bone rescue
  • drug discovery
  • miRNA–mRNA interactions
  • small molecule screening
  • virtual screening models

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