N-苯甲基靛红肟类JNK3抑制剂的分子对接及3D-QSAR研究

摘要/Abstract

摘要：

作为参与调控细胞生理功能的关键因子的c-Jun N-末端激酶, 与多种人类疾病的发生发展密切相关。本文运用低能构象搜索及分子对接方法得到的两组构象, 对N-苯甲基靛红肟类化合物进行三维定量构效关系 (3D-QSAR) 研究。结果表明, 基于分子对接构象, 以立体场、静电场、氢键供体场和氢键受体场组合得到的CoMSIA模型最佳, 相应的统计学参数: 交叉验证相关系数q²为0.759, 相关系数r² 为0.966, 测试集的相关系数r²_pred为 0.703。根据RB方法所得到的CoMSIA模型的三维等值线图, 总结出对抑制剂活性起关键作用的因素: 化合物的N取代基及R6位处于残基Ile70、Asp150、Ala151、Asn152和Ser193组成的疏水性空腔, 因此引入体积较大的取代基有利于活性的提高, 同时在N取代基上加以吸电子或氢键受体基团的取代将有助于提高抑制剂活性。靛红环位于负电荷残基Glu147附近, 引入供电子或氢键供体基团有利于抑制剂活性的提高。同时结果之间可以相互解释并验证彼此的有效性, 可为设计高特异性高活性的 JNK3抑制剂提供线索和参考。

关键词: JNK3, N-苯甲基靛红肟类化合物, 三维定量构效关系研究, 分子对接

Abstract:

The c-Jun N-terminal kinase (JNK) is involved in a variety of important cellular processes and aberrant JNK activity is associated with many human diseases.The ligand-based and receptor-based alignment rules were used to build 3D-QSAR modelsfor a series of N-benzyl isatin oximes JNK inhibitors. The best models were obtained for the receptor-based alignment with CoMSIA combining steric (S), electrostatic (E), and hydrogen bond donor (D) and hydrogen bond acceptor (A) fields (q² = 0.759, r² = 0.966, r²_pred= 0.703). Based on the contour maps of RB CoMSIA model, some key structural factors responsible for inhibitory activity were investigated. Large groups at N-substituent or R6 position are preferred to interact with hydrophobic residues Ile70, Asp150, Ala151, Asn152 and Ser193. Electron-donating or hydrogen bond donor groups on the isatin ring would form polar and hydrogen bond with the negative-charged residue Glu147. In addition, electron-withdrawing groups or hydrogen bond acceptor group near the N-substituent would enhance inhibitory activity. The results are in good accordance and complementary to each other. The developed models could provide guidance in the rational design of more potent and selective JNK inhibitors.

Key words: JNK3, N-benzyl isatin oximes, 3D-QSAR, Molecular docking

中图分类号:

R916

Supporting: Foundation items: Beijing Natural Science Foundation (Grant No. 2123062), Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20121103120008) and Science and Technology Foundation of Beijing University of Technology (Grant No. ykj-2012-8725).
^*Corresponding author. Tel.: 86-10-67391667; Fax: 86-10-67391667

周玥, 张娜^*, 钟儒刚 . N-苯甲基靛红肟类JNK3抑制剂的分子对接及3D-QSAR研究[J]. .

Yue Zhou, Na Zhang^*, Rugang Zhong. Docking and 3D-QSAR studies of N-benzyl isatin oximes as JNK3 inhibitors[J]. .

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