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.

Design, Synthesis and Biological Evaluation of 4‐Amino‐N‐(4‐aminophenyl)benzamide Analogues of Quinoline‐Based SGI‐1027 as Inhibitors of DNA Methylation

“…Noteworthy, the finding that part C fits into the adenine pocket of the cofactor is in agreement with the results obtained by induced-fit docking of SGI-1027 in the MTase domain of mDnmt3A,[14] even though part A is differently positioned compared with our docking result. In particular, the pyrimidine moiety (C) of SGI-1027 was found well superimposable to the six-membered ring of the adenine of AdoHcy (Figure 1, right-hand zoom).…”

Role of computer-aided drug design in modern drug discovery

“…Remarkably, the binding scores obtained for SGI-1027 were in excellent agreement with the published experimental results, validating the docking models. Moreover, the docking result of CBC12 corroborates the proposed inhibitory mechanism for DNMTs which suggests the use of ''long'' scaffolds in the design of DNMT inhibitors (Yoo et al 2013). …”

Computational fishing of new DNA methyltransferase inhibitors from natural products

“…7b and Fig. 7c) docking studies with known DNMTis [43,45,72]. These results suggest the potential application of these NPs in anticancer therapies through the reduction of DNMTs activity.…”

“…Residues involved in the inhibition mechanism of DNMT1 and DNMT 3A [72,74], such as, Phe-1145, Glu-1168, Glu-1169, Cys-1191, Glu-1266 and Val-1580 showed distances of less than 4 Å with selected NPs on 3SWR binding site.…”