Prediction of the binding mechanism of a selective DNA methyltransferase 3A inhibitor by molecular simulation

• Published in: Scientific reports Vol. 14; no. 1; pp. 13508 - 9
• Main Authors: Kudo, Genki, Hirao, Takumi, Harada, Ryuhei, Hirokawa, Takatsugu, Shigeta, Yasuteru, Yoshino, Ryunosuke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114; 639/638/309/2144; 639/638/309/2420; Binding Sites; Cytosine; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1 - antagonists & inhibitors; DNA (Cytosine-5-)-Methyltransferase 1 - chemistry; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors; DNA (Cytosine-5-)-Methyltransferases - chemistry; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; DNA methyltransferase; DNA Methyltransferase 3A; DNMT1 protein; DNMT3A; Drug development; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Epigenetics; Free energy; Gene regulation; Humanities and Social Sciences; Humans; Methionine; Molecular Docking Simulation; Molecular Dynamics Simulation; multidisciplinary; Protein Binding; Protein inhibitor; Protein structure; Science; Science (multidisciplinary); Selective inhibitor; Protein inhibitor; DNA methyltransferase; Molecular dynamics simulation; Selective inhibitor; DNMT3A
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-64236-9

DNA methylation is an epigenetic mechanism that introduces a methyl group at the C5 position of cytosine. This reaction is catalyzed by DNA methyltransferases (DNMTs) and is essential for the regulation of gene transcription. The DNMT1 and DNMT3A or -3B family proteins are known targets for the inhibition of DNA hypermethylation in cancer cells. A selective non-nucleoside DNMT3A inhibitor was developed that mimics S-adenosyl-l-methionine and deoxycytidine; however, the mechanism of selectivity is unclear because the inhibitor–protein complex structure determination is absent. Therefore, we performed docking and molecular dynamics simulations to predict the structure of the complex formed by the association between DNMT3A and the selective inhibitor. Our simulations, binding free energy decomposition analysis, structural isoform comparison, and residue scanning showed that Arg688 of DNMT3A is involved in the interaction with this inhibitor, as evidenced by its significant contribution to the binding free energy. The presence of Asn1192 at the corresponding residues in DNMT1 results in a loss of affinity for the inhibitor, suggesting that the interactions mediated by Arg688 in DNMT3A are essential for selectivity. Our findings can be applied in the design of DNMT-selective inhibitors and methylation-specific drug optimization procedures.