Insight into the selective binding mechanism of DNMT1 and DNMT3A inhibitors: A molecular simulation study
Insight into the selective binding mechanism of DNMT1 and DNMT3A inhibitors: A molecular simulation study
复制标题
深入了解 DNMT1 和 DNMT3A 抑制剂的选择性结合机制：分子模拟研究
DOI：
10.1039/c9cp02024a
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发表时间：
2019
影响因子：
3.3
通讯作者：
Hou T
中科院分区：
文献类型：
--
作者：
Xie T;Yu J;Fu W;Wang Z;Xu L;Chang S;Wang E;Zhu F;Zeng S;Kang Y;Hou T
DNA甲基转移酶（DNMTs）是一种调节DNA甲基化的酶，被认为是肿瘤治疗的有效靶点。然而，DNMT催化结构域的高度结构保守性对设计特定DNMT亚型的选择性抑制剂构成了巨大挑战。本研究通过分子动力学（MD）模拟、终点自由能计算和伞式采样（US）模拟，揭示了三种代表性DNMT抑制剂对DNMT 1和DNMT 3A结合选择性的分子基础，包括SFG（DNMT 1和DNMT 3A双重抑制剂）、DC-05（DNMT 1选择性抑制剂）和GSKex 1（DNMT 3A选择性抑制剂）。通过分子动力学模拟和结合自由能预测，再现了先前实验中报道的所研究的抑制剂的结合选择性。模拟结果还表明，决定所研究的抑制剂的结合选择性的驱动力源于蛋白质-抑制剂的货车德瓦尔斯相互作用的差异。同时，通过对DNMT 1/DNMT 3A结合口袋中几个非保守残基的自由能分解，发现它们的贡献是决定DNMT抑制剂结合选择性的关键因素，尤其是Val 1580/Trp 893、Asn 1578/Arg 891和Met 1169/Val 665。此外，通过US模拟预测的平均力势进一步验证了所研究的抑制剂的结合偏好。本研究为合理设计以DNMT 1和DNMT 3A为靶点的新型选择性抑制剂提供了有价值的信息。
DNA methyltransferases (DNMTs), responsible for the regulation of DNA methylation, have been regarded as promising drug targets for cancer therapy. However, high structural conservation of the catalytic domains of DNMTs poses a big challenge to design selective inhibitors for a specific DNMT isoform. In this study, molecular dynamics (MD) simulations, end-point free energy calculations and umbrella sampling (US) simulations were performed to reveal the molecular basis of the binding selectivity of three representative DNMT inhibitors towards DNMT1 and DNMT3A, including SFG (DNMT1 and DNMT3A dual inhibitors), DC-05 (DNMT1 selective inhibitor) and GSKex1 (DNMT3A selective inhibitor). The binding selectivity of the studied inhibitors reported in previous experiments is reproduced by the MD simulation and binding free energy prediction. The simulation results also suggest that the driving force to determine the binding selectivity of the studied inhibitors stems from the difference in the protein–inhibitor van der Waals interactions. Meanwhile, the per-residue free energy decomposition reveals that the contributions from several non-conserved residues in the binding pocket of DNMT1/DNMT3A, especially Val1580/Trp893, Asn1578/Arg891 and Met1169/Val665, are the key factors responsible for the binding selectivity of DNMT inhibitors. In addition, the binding preference of the studied inhibitors was further validated by the potentials of mean force predicted by the US simulations. This study will provide valuable information for the rational design of novel selective inhibitors targeting DNMT1 and DNMT3A.