4,5,6-三取代嘧啶苯磺酰脲类化合物的生物活性、分子对接与3D-QSAR关系研究

Biological Activity, Molecular Docking and 3D-QSAR Research of N-(4,5,6-Trisubstituted Pyrimidin-2-yl)-N'-benzenesulfonylureas

用柔性分子对接方法(FlexX)将15个4,5,6-三取代嘧啶苯磺酰脲化合物以及3个不含5-位取代嘧啶苯磺酰脲化合物(分别为4,6-双取代嘧啶和4-取代嘧啶)和乙酰羟酸合成酶(AHAS)活性口袋进行了对接,对接程序预测的抑制剂和酶之间的相互作用能与抑制活性之间有一定的相关性,相关系数为0.660.然后采用比较分子相似性指数分析(CoMSIA)对27个新型4,5,6-三取代嘧啶苯磺酰脲类化合物的除草活性进行三维定量构效关系(3D-QSAR)研究.建立了三维定量构效关系CoMSIA模型,立体场、静电场和氢键的贡献分别为47.3%,32.8%,19.9%.交叉验证系数q2值为0.520.根据CoMSIA模型的立体场、静电场、氢键给体场三维等值线图不仅直观地解释了结构与活性的关系,并且与用FlexX预测的结合模式相一致,证明了我们预测的结合模式是可靠的,为进一步设计高活性的标题化合物提供较好的理论指导.

Fifteen N-（4,5,6-trisubstituted pyrimidin-2-yl）-N′-benzenesulfonylureas and three analogous benzenesulfonylureas without 5-substituent at pyrimidine moiety were studied on a flexing molecular docking method （flexX） according to their biological activity to the active site of acetohydroxyacid synthase （AHAS）. The predicted binding affinities of the molecules were found to be linearly relevant to their experimental activities （R=0.660）. Then 27 N-（4,5,6-trisubstituted pyrimidin-2-yl）-N′-benzenesulfonylureas were studied on comparative molecular similarity index analysis. The results showed that the contribution of 2 steric, electrostatic and H-bond donor was 47.3%, 32.8% and 19.9%, respectively. The cross-validated q was 0.520. The results indicate that the 3D-QSAR model is significant and has good predictability, providing useful information for designing new good activity AHAS inhibitors prior to their synthesis.