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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Insights into structural features of HDAC1 and its selectivity inhibition elucidated by Molecular dynamic simulation and Molecular Docking
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Insights into structural features of HDAC1 and its selectivity inhibition elucidated by Molecular dynamic simulation and Molecular Docking

机译：分子动态模拟和分子对接阐明HDAC1的结构特征及其选择性抑制的见解及其选择性抑制

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摘要

Histone deacetylases (HDACs) are a family of proteins whose main function is the removal of acetyl groups from lysine residues located on histone and non-histone substrates, which regulates gene transcription and other activities in cells. HDAC1 dysfunction has been implicated in cancer development and progression; thus, its inhibition has emerged as a new therapeutic strategy. Two additional metal binding sites (Site 1 and Site 2) in HDACs have been described that are primarily occupied by potassium ions, suggesting a possible structural role that affects HDAC activity. In this work, we explored the structural role of potassium ions in Site 1 and Site 2 and how they affect the interactions of compounds with high affinities for HDAC1 (AC1OCG0B, Chlamydocin, Dacinostat and Quisinostat) and SAHA (a pan-inhibitor) using molecular docking and molecular dynamics (MD) simulations in concert with a Molecular-Mechanics-Generalized-Born-Surface-Area (MMGBSA) approach. Four models were generated: one with a potassium ion (K + ) in both sites (HDAC1 k ), a second with K + only at site 1 (HDAC1 ks1 ), a third with K + only at site 2 (HDAC1 ks2 ) and a fourth with no K + (HDAC1 wk ). We found that the presence or absence of K + not only impacted the structural flexibility of HDAC1, but also its molecular recognition, consistent with experimental findings. These results could therefore be useful for further structure-based drug design studies addressing new HDAC1 inhibitors. ?2018, ?2018 Informa UK Limited, trading as Taylor & Francis Group.
机译：组蛋白脱乙酰酶（HDACs）是一种蛋白质家族，其主要功能是从位于组蛋白和非组蛋白基质上的赖氨酸残基的除去乙酰基，其调节基因转录和细胞中的其他活性。 HDAC1功能障碍涉及癌症发展和进展;因此，其抑制作为作为一种新的治疗策略。已经描述了主要由钾离子占据的HDAC中的两种附加金属结合位点（位点1和部位2），这表明可能影响HDAC活性的结构作用。在这项工作中，我们探讨了钾离子在现场1和部位2中的结构作用以及它们如何利用分子对HDAC1（AC1OCG0B，衣原体，Dacinostat和Quisinostat）和Saha（泛抑制剂）的高亲和力的相互作用。使用分子与分子 - 机械通用出生 - 表面积（MMGBSA）接近的音乐会的对接和分子动力学（MD）模拟。产生四种模型：在两个位点（HDAC1 K）中具有钾离子（K +），仅在位点1（HDAC1 KS1）的k +，仅在部位2（HDAC1 KS2）和K +中第四个没有K +（HDAC1 WK）。我们发现，k +的存在或不存在不仅影响了HDAC1的结构灵活性，也不是其分子识别，这与实验结果一致。因此，这些结果可用于解决新的HDAC1抑制剂的进一步结构的药物设计研究。 ？2018年，？2018年Informa Informa Limited，贸易为泰勒和弗朗西斯集团。

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