NMDA受体非竞争性拮抗剂的3D-QSAR研究

3D-QSAR studies on a series of NMDA receptor noncompetitive antagonists

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。

The N-methyl-D-aspartate（NMDA） receptor,one of ionotropic glutamate receptors,plays a major role in glutamate neuronal excitotoxicity,thus the applications of NMDA antagonists have been paid more attention.To explore the three-dimensional quantitative structure-activity relationships（3D-QSAR） of a class of NMDA receptor noncompetitive antagonists for glycine（Gly） binding site, comparative molecular field analysis（CoMFA） was performed on a set of 34 1,4-dinhydro-quinoxaline-2,3-diones.The successful ComFA model yielded a cross-validated q^2 value of 0.566 with optimal number of components of 6,a non-cross-validated r^2 value of 0.969,a standard error of estimate of 0.236,and the contributions of steric and electrostatic fields to bioactivity were 62.3%and 37.7%respectively.The results obtained were graphically interpreted in terms of field contour maps,which indicated that it can increase the bioactivity of the type of compounds when decreased the bulk of substituent group or increased the positive charge of substituent group at the 2 and 3 positions of phenyl ring of 1,4-dihydro-quinoxaline-2,3-diones.The obtained CoMFA model was validated to have good stability and reasonable predictability and the results not only lead to better understanding of structural requirements of NMDA receptor noncompetitive antagonists but also can be helpful in the design of new potent antagonists.