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

Advanced Science
Zhenjian ZhuoBao-Ting Zhang

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 ...Continue Reading

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Citations

Jul 1, 2020·ACS Applied Materials & Interfaces·Shuaijian NiGe Zhang
Apr 4, 2021·International Journal of Molecular Sciences·Zihao ChenGe Zhang
Jul 17, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Amit Kumar RaiVenkata Naga Srikanth Garikipati

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Methods Mentioned

BETA
xenografts
interaction assay
transfection
PCR
enzyme linked immunosorbent assay
ELISA
isothermal titration calorimetry
chip
Transgenic
size exclusion chromatography

Software Mentioned

miRanda
NPDock
BIOQUANT OSTEO
Mfold
RNAfold
RDkit
UCSC genome browser
Autodock Vina
Python RDkit
AutoDockTools

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