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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Screening of novel histone deacetylase 7 inhibitors through molecular docking followed by a combination of molecular dynamics simulations and ligand-based approach
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Screening of novel histone deacetylase 7 inhibitors through molecular docking followed by a combination of molecular dynamics simulations and ligand-based approach

机译：通过分子对接筛选新型组蛋白脱乙酰酶7抑制剂，然后进行分子动力学模拟和基于配体的方法的组合

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Histone acetylation/deacetylation is a key mechanism for transcription regulation which plays an important role in control of gene expression, tissue growth, and development. In particular, histone deacetylase 7 (HDAC7), a member of class lla HDACs, is crucial to maintain cell homeostasis, and HDAC7 has emerged as a new target for cancer therapy. In this study, molecular docking was applied to screen candidate inhibitors and 21 compounds were found. Following the 50 ns molecular dynamics simulations and binding free energy calculation, ZINC00156160, ZINC01703144, ZINC04293665, and ZINC13900201 were identified as potential HDAC7 inhibitors, which would provide a sound starting point for further studies involving molecular modeling coupled with biochemical experiments. Meanwhile, similarity computation and substructure search were combined, and then we found that compounds sharing common backbone "CC(=O)N[C@@H](CSc1ccccc1)C(=O)O" could be efficient to inhibit the bioactivity of HDAC7. Then comparative molecular similarity indices analysis (CoMSIA) techniques were implemented to investigate the relationship between properties of the substituent group and bioactivities of small molecules. The CoMSIA model exhibited powerful predictivity, with satisfactory statistical parameters such as q2 of 0.659, R2 of 0.952, and F of 268.448. Contour maps of the CoMSIA model gave insight into the feature requirements of the common backbone for the HDAC7 inhibitory activity. Finally, details of designing novel HDAC7 inhibitors were confirmed by a combination of receptor-based docking and ligand-based structure-activity relationship.
机译：组蛋白乙酰化/脱乙酰化是转录调节的关键机制，其在控制基因表达，组织生长和发育中起着重要作用。特别地，组蛋白脱乙酰酶7（HDAC7），LLA HDAC类别，对于维持细胞稳态至关重要，HDAC7已成为癌症治疗的新靶标。在该研究中，将分子对接应用于筛选候选抑制剂，并发现21种化合物。在50 ns分子动力学模拟和结合的自由能量计算之后，ZINC00156160，锌01703144，锌04293665和锌13900201被鉴定为潜在的HDAC7抑制剂，这将为进一步研究提供涉及与生化实验的分子建模的进一步研究的声音起点。同时，组合了相似性计算和子结构搜索，然后我们发现共享公共骨干网“CC（= O）N [C @@ H]（CSC1CCCCC1）C（= O）O”的化合物可以有效地抑制生物活性HDAC7。然后实施比较分子相似索引分析（COMSIA）技术以研究取代基组和小分子生物活性的关系。 COMSIA模型表现出强大的预测性，令人满意的统计参数，例如0.659，R2为0.952的Q2，F为268.448。 COMSIA模型的轮廓图对HDAC7抑制活动的公共骨干的特征要求具有深入了解。最后，通过基于受体的对接和基于配体的结构 - 活性关系的组合确认了设计新型HDAC7抑制剂的细节。

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