二肽肽酶IV抑制剂的三维定量构效关系研究

Quantitative Structure-activity Relationship of Dipeptidyl Peptidase IV Inhibitors

二肽肽酶IV是一类用于治疗II型糖尿病具有潜在价值的关键酶, 很多此类酶的抑制剂用于处理此病具有相当好的有效性. 一系列N-取代的甘氨酰氰基吡咯烷衍生物对于二肽肽酶具有高的活性和选择性. 我们使用比较分子力场分析方法建立DPP-IV 抑制剂——N-取代的甘氨酰氰基吡咯衍生物的三维定量构效关系, 该模型为设计用于治疗II 型糖尿病的高效DPP-IV抑制剂提供结构信息. CoMFA模型的交叉验证相关系数q2=0.575, 非交叉验证相关系数r2=0.981,绝对误差S=0.184, F9.68=388.5. 使用七个预测集检验了模型的预测能力. 所得的模型解释了已有的构效关系, 并对同类化合物有较好的预测能力, 该模型可用于指导新型的DPP-IV 抑制剂的设计与优化.

Dipeptidyl peptidase IV is a critical enzyme of potential value in the treatment of type 2 diabetes. A 3D-QSAR model was obtained by using comparative molecular field analysis (CoMFA) on a series of de- rivatives N-substituted-glycyl-2-cyanopyrrolidine with highly potent and selective inhibition for dipeptidyl peptidase IV. The final QSAR model was developed by CoMFA analyses, with q2=0. 575 and r2=0. 981. The predictive ability of this model was validated by seven compounds that were not included in the training set. The robust QSAR model and its three-dimensional contour map provided guidelines to build novel com- pounds with new scaffold and structural optimization of current molecules.