物理化学学报 >> 2015, Vol. 31 >> Issue (12): 2395-2404.doi: 10.3866/PKU.WHXB201510142

生物物理化学 上一篇    下一篇

芳香噻嗪类衍生物作为选择性醛糖还原酶抑制剂的分子对接和基于受体的三维定量构效关系研究

张淑贞,郑超,朱长进*()   

  • 收稿日期:2015-08-10 发布日期:2015-12-04
  • 通讯作者: 朱长进 E-mail:zcj@bit.edu.cn
  • 基金资助:
    国家自然科学基金(21272025);北京市科学技术委员会(Z131100004013003)

Molecular Docking and Receptor-Based 3D-QSAR Studies on Aromatic Thiazine Derivatives as Selective Aldose Reductase Inhibitors

Shu-Zhen. ZHANG,Chao. ZHENG,Chang-Jin. ZHU*()   

  • Received:2015-08-10 Published:2015-12-04
  • Contact: Chang-Jin. ZHU E-mail:zcj@bit.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(21272025);Science and Technology Commission of Beijing,China(Z131100004013003)

摘要:

芳香噻嗪类衍生物被证明是一类选择性较好的高活性醛糖还原酶抑制剂(ARIs).本文对44个芳香噻嗪类化合物进行了分子对接(docking)和三维定量构效关系(3D-QSAR)研究,并探索了此类化合物与醛糖还原酶(ALr2)的作用机理.醛糖还原酶与醛还原酶(ALR1)活性位点的叠加结果显示, ALr2中残基Leu 300和Cys298的存在是化合物1m具有高选择性的原因.分别建立了比较分子场分析方法(CoMFA, q2 = 0.649, r2 =0.934; q2:交叉验证相关系数, r2:非交叉验证相关系数)和比较分子相似性指数分析方法(CoMSIA, q2 = 0.746, r2 = 0.971)模型,并对影响此类化合物生物活性的结构进行了鉴定.结果显示,两个模型均具有较高预测能力,并通过测试集中的7个化合物进行了验证,其中CoMFA模型和CoMSIA模型的预测相关系数(rPred2)分别为0.748和0.828. 3D-QSAR模型中的三维等值线图表明,在化合物1m的苄基环上C3和C4位置以及苯并噻嗪母核上C5和C7位置进行改进可能对生物活性的提高有利,此预测与我们前期报道的苯并噻嗪母核C7位改进结果一致.本文所建3D-QSAR模型能够在理性设计具有更高生物活性的新型ARIs中发挥重要作用.

关键词: 醛糖还原酶抑制剂, 分子对接, 三维构效关系, 选择性, 芳香噻嗪类衍生物

Abstract:

Aromatic thiazine derivatives were proved to be potent aldose reductase inhibitors (ARIs) with high selectivity for aldose reductase (ALr2) over aldehyde reductase (ALR1). Molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies are conducted on a dataset of 44 molecules to explore the interactions between aromatic thiazine derivatives and ALr2. The superposition of ALr2 and ALR1 active sites indicate that residues Leu 300 and Cys 298 from ALr2 may explain the good selectivity of the most active compound 1m. The comparative molecular field analysis (CoMFA) model (q2 = 0.649, r2 = 0.934; q2: cross-validated correlation coefficient, r2: non-cross-validated correlation coefficient) and comparative molecular similarity indices analysis (CoMSIA) model (q2 = 0.746, r2 = 0.971), based on the docking conformations of these compounds, are obtained to identify the key structures impacting their inhibitory potencies. The predictive power of the developed models is further validated by a test set of seven compounds, resulting in predictive rPred2 values of 0.748 for CoMFA and 0.828 for CoMSIA. 3D contour maps, drawn from 3D-QSAR models, reveal that future modifications of substituents at the C3 and C4 positions of the benzyl ring and the C5 and C7 positions of the benzothiazine-1, 1-dioxide core might be favorable for improving the biological activity, which are in good accordance with the C7 modification results reported in our earlier work. The information rendered by 3DQSAR models could be helpful in the rational design of novel ARIs with good inhibitory activity to treat diabetic complications in the future.

Key words: Aldose reductase inhibitor, Molecular docking, 3D-QSAR, Selectivity, Aromatic thiazine derivative

MSC2000: 

  • O641