1,2-萘醌类化合物抑制PTP1B的三维定量构效关系研究

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.

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

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.