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Abstract：
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.
摘要：
DNA甲基化是在胞嘧啶的C5位置引入甲基的表观遗传机制。该反应由DNA甲基转移酶（DNMT）催化，对于调节基因转录至关重要。DNMT1和DNMT3A或-3B家族蛋白是抑制癌细胞中DNA超甲基化的已知靶标。开发了一种模拟S-腺苷-1-蛋氨酸和脱氧胞苷的选择性非核苷DNMT3A抑制剂；然而，选择性机制尚不清楚，因为缺乏抑制剂-蛋白质复合物结构的测定。因此,我们进行了对接和分子动力学模拟,以预测DNMT3A与选择性抑制剂缔合形成的复合物的结构.我们的模拟,结合自由能分解分析，结构同工型比较，残留扫描显示DNMT3A的Arg688参与了与该抑制剂的相互作用，它对结合自由能的重大贡献证明了这一点。Asn1192在DNMT1中相应残基的存在导致对抑制剂的亲和力丧失，这表明DNMT3A中Arg688介导的相互作用对选择性至关重要。我们的发现可应用于DNMT选择性抑制剂的设计和甲基化特异性药物优化程序。
