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.
Highlights
DNA methyltransferases (DNMTs) catalyze the transfer of a methyl group from S-adenosyl-L-methionine (SAM or AdoMet) to the carbon-5 position of cytosine residues that result in an epigenetic change [1]
For DNMT1, the whole structure, and only the catalytic domain were used during induced-fit docking (IFD)
The different binding sites of DNMT1 and DNMT3A were explored for SGI-1027 and CBC12
Summary
DNA methyltransferases (DNMTs) catalyze the transfer of a methyl group from S-adenosyl-L-methionine (SAM or AdoMet) to the carbon-5 position of cytosine residues that result in an epigenetic change [1]. Three active forms of DNMT have been identified in mammals: DNMT1, DNMT3A/3B, and DNMT3L. DNMT1 which is the most abundant of the three is involved in the maintenance of methylation patterns, whereas DNMT3A and DNMT3B are responsible for de novo methylation [2,3]. DNMT3L is required for the catalytic activity of DNMT3A and DNMT3B, though it lacks catalytic activity because of the absence of conserved catalytic residues [4,5]. DNMT inhibitors are promising new drugs for the treatment of diseases such as cancer and brain disorders [6,7]
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