國家衛生研究院 NHRI:Item 3990099045/12299
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    题名: Identification of novel quinoline inhibitor for EHMT2/G9a through virtual screening
    作者: Chandar Charles, MR;Mahesh, A;Lin, SY;Hsieh, HP;Dhayalan, A;Coumar, MS
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: G9a (also known as EHMT2 - Euchromatin histone methyltransferase 2) is a protein lysine methyltransferase which introduces methylation modification in variety of proteins including histones. G9a catalyzes the dimethylation of lysine 9 on histone 3 (H3K9me2) which is a repressive epigenetic modification. H3K9me2 is associated with the silencing of several genes including tumor suppressor genes in many cancers and hence G9a is a well characterized drug target for cancer therapy. Here, we report the discovery of CSV0C018875 as a novel quinoline based G9a inhibitor through virtual screening strategy from a HTS database. Sub-structure querying based on the known G9a inhibitors, followed by docking based virtual screening, led to the identification of CSV0C018875 as G9a inhibitor. We found that CSV0C018875 inhibits the activity of G9a in both enzyme and cell based assays. Importantly, the toxicity of CSV0C018875 is much lesser than that of the well-studied G9a inhibitor, BIX-01294. Molecular dynamics simulations shows that CSV0C018875 binds deeper inside the active site cavity of G9a, which facilitates the tight binding and also increases the compounds residence time, which in turn reflects better G9a inhibition. The novel quinoline CSV0C018875 could be further optimized to improve the ADME as well pharmacodynamic property.
    日期: 2020-01
    關聯: Biochimie. 2020 Jan;168:220-230.
    Link to: http://dx.doi.org/10.1016/j.biochi.2019.11.006
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0300-9084&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000503444300020
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85075503120
    显示于类别:[謝興邦] 期刊論文
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