哒嗪酮类（1，3）-β-D-葡聚糖合成酶抑制剂的三维定量构效关系研究

摘要

Using comparative molecular field analysis (CoMFA) and comparative molecular similari‐ty indices analysis (CoMSIA) ,three dimensional structure‐activity relationship(3D‐QSAR)studies were carried out on a series of pyridazinone (1 ,3)‐β‐D‐glucan synthase (GS) small molecule inhibitors .The 3D‐QSAR models were shown to have excellent prediction (CoMFA :the cross‐validation coefficient q2 =0 .585 ,and the correlation coemcient r2 = 0 .999 ,C0MSIA :the cross‐validation coefficient q2 =0 .534 , and the correlation coeficient r2 =0 .987) .3D contour maps suggested that hydrophobic substituents and hydrogen bond acceptor groups on the core part would decrease antiviral activity .This study may help to design novel selective antagonists of GS with desired activity .%为了探讨哒嗪酮类（1，3）‐β‐D‐葡聚糖合成酶抑制剂的结构与其药理活性的相互关系，本次研究拟对20个哒嗪酮类化合物分别利用比较分子力场分析法（CoM FA ）和比较分子相似性指数分析法（CoMSIA）进行三维定量构效关系（3D‐QSAR）的研究，并各自建立起相应的模型．通过对计算结果进行分析发现：利用CoM FA建立起来的模型相关系数 r2＝0．999，交叉验证系数q2＝0．585；而CoMSIA模型的相关系数r2＝0．987，交叉验证系数q2＝0．534，均满足标准模型的需要．而将这2种方法建立起来的3D‐QSAR模型用于哒嗪酮类化合物的抗真菌活性的预测，也均表现出良好的效果．并且从等值面图的分析可以看出，在哒嗪酮类（1，3）‐β‐D‐葡聚糖合成酶抑制剂的结构上适当引入一些疏水基团和氢键受体可以增强该类化合物的抗真菌活性．