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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >3D-QSAR studies of HDACs inhibitors using pharmacophore-based alignment.
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3D-QSAR studies of HDACs inhibitors using pharmacophore-based alignment.

机译：HDACs抑制剂的3D-QSAR研究使用基于药效团的比对方法。

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摘要

Histone deacetylases (HDACs) enzyme is a promising target for the development of anticancer drugs. The enzyme-bound conformation of Trichostatin A (TSA) (PDB ID:1C3R) as an inhibitor of HDACs was used to manually construct a pharmacophore model. This model was then successfully used to identify the bioactive conformation and align flexible and structurally diverse molecules. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on hydroxamate-based HDACs inhibitors based on phamacophore alignment. The best predictions were obtained with CoMFA standard model (q(2) = 0.726, r(2) = 0.998) and CoMSIA model combined with steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields (q(2) = 0.610, r(2) = 0.995). Both of the models were validated by an external test set, which gave a satisfactory predictive r(2) value of 0.800 and 0.732, respectively. Graphical interpretation of the results revealed important structural features of the inhibitors related to the active site of HDACs. The results may be exploited for further design and virtual screening for some novel HDACs inhibitors.
机译：组蛋白脱乙酰基酶（HDACs）酶是抗癌药物开发的有希望的目标。作为HDAC抑制剂的Trichostatin A（TSA）（PDB ID：1C3R）的酶结合构象用于人工构建药效团模型。然后，该模型成功用于鉴定生物活性构象并排列柔性和结构多样的分子。在基于吞噬体排列的基础上，对基于异羟肟酸酯的HDACs抑制剂进行了比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）。使用CoMFA标准模型（q（2）= 0.726，r（2）= 0.998）和CoMSIA模型与空间，静电，疏水，氢键供体和受体场（q（2）= 0.610，r （2）= 0.995）。这两个模型都通过外部测试集进行了验证，该模型分别给出了令人满意的r（2）预测值0.800和0.732。结果的图形解释揭示了与HDAC活性位点有关的抑制剂的重要结构特征。该结果可用于进一步设计和虚拟筛选某些新型HDACs抑制剂。

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