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NMDA受体(N-methyl-D-aspartate receptor)是离子型谷氨酸受体(ionotropic glutamate receptors,iGluRs)的一亚型,对谷氨酸的神经兴奋毒性起关键性作用,因此对于NMDA受体拮抗剂的应用已引起广泛重视。本研究选用NMDA受体甘氨酸位点拮抗剂1,4-二氢喹喔啉-2,3-二酮衍生物(QXs)为研究对象,采用比较分子场分析法(CoMFA)建立34个NMDA受体拮抗剂的三维定量构效关系(3D-QSAR)模型。此CoMA模型的交叉验证相关系数(q~2)0.566,最佳主成分数(ONC)6,非交叉验证相关系数(r~2)0.969,标准方差(SEE)0.236,立体场和静电场贡献值分别为62.3%和37.7%,研究结果可用分子场等势图直观表示。分子场等势图结果表明,在1,4-二氢喹喔啉-2,3-二酮衍生物苯环2,3位,减少取代基体积或增加取代基的正电性,可以提高该类化合物的活性。所建模型的预测能力和拟合能力较好,不仅了解清楚NMDA受体非竞争性拮抗剂的结构特征,还为设计活性更高的受体拮抗剂提供理论依据。
NMDA receptor (N-methyl-D-aspartate receptor) is a subtype of ionotropic glutamate receptors (iGluRs), which plays a key role in the excitotoxicity of glutamate. Therefore, NMDA receptor The application of body antagonists has drawn wide attention. In this study, NMDA receptor glycine site antagonist 1, 4-dihydroquinoxaline-2,3-dione derivatives (QXs) were selected as the research object, 34 NMDA receptors were established by comparative molecular field analysis (CoMFA) Three Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Models of Body Antagonists. The cross validation correlation coefficient (q ~ 2) 0.566, the optimal principal component (ONC) 6, the non - cross validation correlation coefficient (r ~ 2) of 0.969, the standard deviation of variance (SEE) of 0.236 and the contributions of the three - dimensional field and the electrostatic field The values were 62.3% and 37.7%, respectively. The results of the study can be directly expressed by the equipotential maps of molecular fields. The results of the equipotential plot of the molecular field indicate that reducing the substituent volume or increasing the positive charge of the substituent at the benzene ring 2,3 position of the 1,4-dihydroquinoxaline-2,3-dione derivative can improve the Class compound activity. The model has good predictive ability and fitting ability, which can not only understand the structural characteristics of non-competitive NMDA receptor antagonists, but also provide theoretical basis for the design of more active receptor antagonists.