title: Molecular modeling studies of the novel inhibitors of DNA methyltransferases SGI-1027 and CBC12: implications for the mechanism of inhibition of DNMTs.
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.
authors: National Leading Research Lab of Molecular Modeling & Drug Design, College of Pharmacy, Division of Life and Pharmaceutical Sciences, and Global Top5 Research Program, Ewha Womans University, Seoul, Korea.
authors: Jakyung
authors: J
authors: Yoo
authors: Sun
authors: S
authors: Choi
authors: José L
authors: JL
authors: Medina-Franco
mesh_terms: D000595:Amino Acid Sequence; D000634:Aminoquinolines / Q000378:metabolism / Q000494:pharmacology*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000090205:DNA Methyltransferase 3A; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010797:Phthalimides / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000634:Aminoquinolines; C000717967:DNMT3A protein, human; D004791:Enzyme Inhibitors; D010797:Phthalimides; D011743:Pyrimidines; C581203:SGI-1027; C037431:phthalimide; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619380:DNMT1 protein, human
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