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Molecular Modeling Studies of the Novel Inhibitors of DNA Methyltransferases SGI-1027 and CBC12: Implications for the Mechanism of Inhibition of DNMTs

Title
Molecular Modeling Studies of the Novel Inhibitors of DNA Methyltransferases SGI-1027 and CBC12: Implications for the Mechanism of Inhibition of DNMTs
Authors
Yoo J.Choi S.Medina-Franco J.L.
Ewha Authors
최선유자경
SCOPUS Author ID
최선scopus
Issue Date
2013
Journal Title
PLoS ONE
ISSN
1932-6203JCR Link
Citation
vol. 8, no. 4
Indexed
SCIE; SCOPUS WOS scopus
Abstract
DNA methylation is an epigenetic modification that regulates gene expression by DNA methyltransferases (DNMTs). Inhibition of DNMTs is a promising approach for cancer therapy. Recently, novel classes of the quinolone-based compound, SGI-1027, and RG108-procainamide conjugates, CBC12, have been identified as potent DNMT inhibitors. In this work, we report comprehensive studies using induced-fit docking of SGI-1027 and CBC12 with human DNMT1 and DNMT3A. The docking was performed in the C-terminal MTase catalytic domain, which contains the substrate and cofactor binding sites, in the presence and absence of other domains. Induced-fit docking predicts possible binding modes of the ligands through the appropriate structural changes in the receptor. This work suggests a hypothesis of the inhibitory mechanisms of the new inhibitors which is in agreement with the reported autoinhibitory mechanism. The insights obtained in this work can be used to design DNMT inhibitors with novel scaffolds. © 2013 Yoo et al.
DOI
10.1371/journal.pone.0062152
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약학대학 > 약학과 > Journal papers
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