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化学学报
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化学学报 ›› 2008, Vol. 66 ›› Issue (2): 188-194. 上一篇    下一篇

研究论文

1,2-萘醌类化合物抑制PTP1B的三维定量构效关系研究

于倩，李艳妮，葛志强   

  1. (天津大学化工学院制药工程系 天津 300072)
  • 投稿日期:2007-03-29 修回日期:2007-08-30 发布日期:2008-01-28
  • 通讯作者: 葛志强

3D-QSAR Analyses of 1,2-Naphthoquinone Derivatives Inhibiting PTP1B

YU Qian LI Yan-Ni GE Zhi-Qiang   

  1. (Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072)
  • Received:2007-03-29 Revised:2007-08-30 Published:2008-01-28
  • Contact: GE Zhi-Qiang

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被引次数

19

蛋白酪氨酸磷酸酶1B (protein tyrosine phosphatase 1B, PTP-1B)是近年来发现的治疗II型糖尿病的新靶点, 1,2-萘醌类化合物对PTP-1B有较好的抑制活性, 具有良好的药用前景. 为了设计出本类化合物抑制效果更好的分子构型, 用比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)对该类化合物进行了三维定量构效关系(3D-QSAR)的研究, 并建立了相关的预测模型. 其中, CoMFA模型的交叉验证相关系数(q2)为0.555, 非交叉验证相关系数(r2)为0.991, 标准偏差(SEE)为0.049, F值为564.910. CoMSIA模型的q2为0.558, r2为0.991, SEE为0.050, F值为542.773. 计算结果表明, 获得的CoMFA和CoMSIA模型具有良好的预测能力, 可以应用于指导该类化合物的设计.

关键词: 1,2-萘醌, 三维定量构效关系, 蛋白酪氨酸磷酸酶1B

Protein tyrosine phosphatase 1B (PTP-1B), has been implicated as a negative regulator of insulin receptor signaling. 1,2-Naphthoquinone skeleton was discovered as a hit toward the PTP-1B inhibitor. Here, 3D-QSAR and molecular modeling was performed on a series of 1,2-naphthoquinone derivatives. Thirty-two compounds were served to establish the model, which was validated by evaluation of an external set of 4 compounds. The best predictions were obtained with the CoMFA steric, electrostatic fields (leave-one-out q2＝0.555, no validation r2＝0.991, standard error of estimate＝0.049, F＝564.910), and with the CoMSIA combined steric, electrostatic, and lipophilic fields (leave-one-out q2＝0.558, no validation r2＝0.991, standard error of estimate＝0.050, F＝542.773). The 3D-QSAR model was then superimposed to the PTP-1B active site, giving direct contour maps of the different fields.

Key words: 1,2-naphthoquinone, 3D-QSAR, protein tyrosine phosphatase 1B