Identification of novel 5-hydroxy-1H-indole-3-carboxylates with anti-HBV activities based on 3D QSAR studies
Identification of novel 5-hydroxy-1H-indole-3-carboxylates with anti-HBV activities based on 3D QSAR studies
复制标题
基于 3D QSAR 研究鉴定具有抗 HBV 活性的新型 5-羟基-1H-吲哚-3-羧酸盐
DOI：
10.1007/s00894-010-0873-7
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发表时间：
2011-08-01
影响因子：
2.2
通讯作者：
Luo, Cheng
中科院分区：
文献类型：
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作者：
Chai, Hui-fang;Liang, Xin-xia;Luo, Cheng
乙肝病毒感染是引起肝硬变和肝细胞癌等肝病的主要原因。在我们之前的研究中，我们发现了具有抗乙肝病毒活性的吲哚类化合物。在这项研究中，我们利用三维定量构效关系(3D QSAR)结合比较分子场分析(CoMFA)和比较分子相似指数分析(CoMSIA)优化了一系列具有较强抗乙肝活性的5-羟基-1H-吲哚-3-羧酸酯。从系统搜索中获得的化合物3的最低能量构象被用作比对的模板，该化合物表现出最强的抗乙肝病毒活性。使用CoMFA标准模型(Q2= 0.689，R2=0.965，见 = 0.082，F = 148.751)和CoMSIA结合的空间、静电、疏水和氢键接受场(Q2= 0.578，R2= 0.973，见 = 0.078，F = 100.342)得到了最好的预测。这两个模型都通过六种化合物的外部测试集进行了验证，得到了令人满意的预测。根据CoMFA和CoMSIA模型及其等高线图的线索，设计合成了另外三个化合物。药理实验表明，新化合物具有较强的抗乙肝病毒活性(IC_(50)：化合物35ais 3.1nμμ/L，化合物3为4.1mgMol/L)。结合3D QSAR研究的线索和3D QSAR模型的进一步验证，新合成的吲哚类化合物的活性得到了很好的解释。此外，这表明CoMFA和CoMSIA模型具有良好的预测能力。
Infection with hepatitis B virus (HBV) is a major cause of liver diseases such as cirrhosis and hepatocellular carcinoma. In our previous studies, we identified indole derivatives that have anti-HBV activities. In this study, we optimize a series of 5-hydroxy-1H-indole-3-carboxylates, which exhibited potent anti-HBV activities, using three-dimensional quantitative structure-activity relationship (3D QSAR) studies with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The lowest energy conformation of compound3, which exhibited the most potent anti-HBV activity, obtained from systematic search was used as the template for alignment. The best predictions were obtained with the CoMFA standard model (q2= 0.689,r2= 0.965, SEE = 0.082, F = 148.751) and with CoMSIA combined steric, electrostatic, hydrophobic and H-bond acceptor fields (q2= 0.578,r2= 0.973, SEE = 0.078, F = 100.342). Both models were validated by an external test set of six compounds giving satisfactory prediction. Based on the clues derived from CoMFA and CoMSIA models and their contour maps, another three compounds were designed and synthesized. Pharmacological assay demonstrated that the newly synthesized compounds possessed more potent anti-HBV activities than before (IC50: compound35ais 3.1 μmol/l, compound3is 4.1 μmol/l). Combining the clues derived from the 3D QSAR studies and from further validation of the 3D QSAR models, the activities of the newly synthesized indole derivatives were well accounted for. Furthermore, this showed that the CoMFA and CoMSIA models proved to have good predictive ability.