黄酮类醛糖还原酶抑制剂的抑制机理研究

为了研究黄酮类醛糖还原酶抑制剂的抑制机理, 选择了31个黄酮类化合物作为训练集, 使用Catalyst软件包构建了此类抑制剂的药效团模型. 并专门针对黄酮类化合物定制了氢键给体和受体模型, 效果优于使用Catalyst内预定义的模型. 最终的药效团模型由两个氢键给体和一个氢键受体组成, 对训练集具有较好预测能力(Correl=0.9013). 此外, 使用InsightII/Affinity对6个黄酮类化合物进行了分子对接研究. 综合药效团模型和分子对接研究的结果, 发现黄酮类化合物的抑制活性主要源于黄酮骨架上的C4’或C3’位的羟基与醛糖还原酶活性口袋中的TYR48、VAL47、GLN49和C7位的羟基与HIS110, TRP111所形成的两组氢键.

Flavonoids with Aldose Reductase Inhibiting Activity: Pharmacophore Modeling and Implications for Mechanism

A three-dimensional pharmacophore model was generated for aldose reductase(ALR2)inhibitors with flavonoid skeleton,using the software Catalyst.Specially customized features of hydrogen-bond acceptor and donor were used in this study,which perform better than the default features of Catalyst.The hypothesis model was scored based on the cost of the hypothesis from the null hypothesis.The final selected pharmacophore model had three features;one hydrogen bond acceptor and two donors.Six flavonoid compounds were used to dock into ALR2 active site,using InsightII/Affinity.Comparison between the pharmacophore model and the docking results suggested that the C7 and C4' hydroxyls on the flavone skeleton were key functional groups influencing ALR2 inhibotory activity,and TYR48,VAL47,GLN49,HIS110,and TRP111 at the active site of ALR2 were the key residues for the binding.