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作为参与调控细胞生理功能的关键因子的c-JunN-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r2pred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。
As a key factor in the regulation of cellular physiological functions of c-Jun N-terminal kinase, and a variety of human diseases is closely related to the occurrence and development. In this paper, three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of N-benzylindenyl oximes were carried out using two conformations obtained from low energy conformational search and molecular docking. The results show that the CoMSIA model based on the three-dimensional field, electrostatic field, hydrogen bond donor field and hydrogen bond acceptor field is the best. The corresponding statistical parameters are as follows: the correlation coefficient of cross validation is 0.759, the correlation coefficient r2 is 0.966, and the correlation coefficient of test set r2pred is 0.703. According to the 3D contour map of the CoMSIA model obtained by the RB method, the factors that play key roles in inhibiting the activity of the inhibitor are summarized as follows: the N substituent of the compound and the hydrophobic group consisting of residues Ile70, Asp150, Ala151, Asn152 and Ser193 at position R6 The introduction of bulky substituents facilitates the increase in activity, while the addition of electron withdrawing or hydrogen bond acceptor groups on the N substituent will help to increase the inhibitory activity. The isatin ring is located near the negatively charged residue Glu147, and introduction of donor or hydrogen donor groups favors an increase in inhibitor activity. At the same time, the results can mutually explain and verify the validity of each other, which can provide clues and reference for the design of high specificity and high activity of JNK3 inhibitors.