@article{47734ee05ecf4bbcb99e23456d7e1390,
title = "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",
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.",
keywords = "bone rescue, drug discovery, miRNA–mRNA interactions, small molecule screening, virtual screening models",
author = "Zhenjian Zhuo and Youyang Wan and Daogang Guan and Shuaijian Ni and Luyao Wang and Zongkang Zhang and Jin Liu and Chao Liang and Yuanyuan Yu and Aiping Lu and Ge Zhang and Bao-Ting Zhang",
note = "Funding Information: Z.Z., Y.W., D.G., S.N., and L.W. contributed equally to this work. This was a joint project which involved three academic units, including The Chinese University of Hong Kong (CUHK) and Institute of Integrated Bioinformedicine and Translational Science, Hong Kong Baptist University (HKBU-IBTS), and Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University (HKBU-TMBJ). This study was supported by the funds from the National Key R&D Program of China (2018YFA0800804), the National Natural Science Foundation Council of China (81702189, 81703049, and 81803374), the Interdisciplinary Research Clusters Matching Scheme of Hong Kong Baptist University (RC-IRCs/17-18/02, RC/IRCs/17-18/04, and RC-IRMS/15-16/01), Hong Kong General Research Fund (14112915, 14100218, 14108816, 12101018, 12102518, HKBU12102914, HKBU12101117, HKBU12136616, and HKBU12103519), Hong Kong Baptist University Strategic Development Fund (SDF13-1209-P01, SDF15-0324-P02(b), and SDF19-0402-P02), Science and Technology Innovation Commission of Shenzhen Municipality Funds (JCYJ20160229210357960), and the direct grant of The Chinese University of Hong Kong (4054220 and 4054138). The authors thank Prof. Matthew D. Disney from Department of Chemistry, The Scripps Research Institute, United States, for his help in providing the assess to Inforna and miRNA motif database servers, which is the basis of the current model. The authors thank Bioinformedicine Service (San Diego, CA, USA) for their help in statistic calculation. Note: Errors in affiliation 5 and 6 were corrected on 8 July 2020 after original online publication. Funding Information: Z.Z., Y.W., D.G., S.N., and L.W. contributed equally to this work. This was a joint project which involved three academic units, including The Chinese University of Hong Kong (CUHK) and Institute of Integrated Bioinformedicine and Translational Science, Hong Kong Baptist University (HKBU‐IBTS), and Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University (HKBU‐TMBJ). This study was supported by the funds from the National Key R&D Program of China (2018YFA0800804), the National Natural Science Foundation Council of China (81702189, 81703049, and 81803374), the Interdisciplinary Research Clusters Matching Scheme of Hong Kong Baptist University (RC‐IRCs/17‐18/02, RC/IRCs/17‐18/04, and RC‐IRMS/15‐16/01), Hong Kong General Research Fund (14112915, 14100218, 14108816, 12101018, 12102518, HKBU12102914, HKBU12101117, HKBU12136616, and HKBU12103519), Hong Kong Baptist University Strategic Development Fund (SDF13‐1209‐P01, SDF15‐0324‐P02(b), and SDF19‐0402‐P02), Science and Technology Innovation Commission of Shenzhen Municipality Funds (JCYJ20160229210357960), and the direct grant of The Chinese University of Hong Kong (4054220 and 4054138). The authors thank Prof. Matthew D. Disney from Department of Chemistry, The Scripps Research Institute, United States, for his help in providing the assess to Inforna and miRNA motif database servers, which is the basis of the current model. The authors thank Bioinformedicine Service (San Diego, CA, USA) for their help in statistic calculation. Publisher copyright: {\textcopyright} 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ",
year = "2020",
month = jul,
doi = "10.1002/advs.201903451",
language = "English",
volume = "7",
journal = "Advanced Science",
issn = "2198-3844",
publisher = "Wiley-VCH Verlag",
number = "13",
}