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采用遗传算法构建了27种人类腺苷受体拮抗剂1,2,4-三唑并[1,5-α]喹喔啉衍生物与受体之间的亲和性的QSAR模型.为得到理想模型,计算了拓扑学、热力学、空间、电子拓扑状态和量子化学描述符.结合这些参数得到最终模型:ENpKi=13.407-0.027*FC-8-0.033*FC-8+0.845*Atype_C_28-19.493*Shadow_XYfrac.计算得到的统计学指标为:LOF=0.291,r2=0.766,ra2dj=0.723,F-test=17.974,PRESS=3.469,CV-r2=0.791.通过对模型进行分析,得到如下结论:降低C-8位亲电、亲核原子的前线电子密度的权重和分子在XY平面的投影分数,增加疏水性原子类型描述符Atpye_C_28的值,都对增加化合物分子与受体的亲和性有利.利用此模型合理的设计了两个新的化合物,并预测具有较高的结合活性.该研究为喹喔啉衍生物作为人类A3腺苷受体拮抗剂的结构改造提供理论指导,并为进一步研究受体与配体亲和性机理奠定理论基础.
A genetic algorithm was used to construct the QSAR model of the affinity between the receptors of 27 human adenosine receptor antagonists, 1,2,4-triazolo [1,5-a] quinoxaline derivatives. The ideal model calculates topological, thermodynamic, space, electronic topological states and quantum chemical descriptors. The final model is derived from these parameters: ENpKi = 13.407-0.027 * FC-8-0.033 * FC-8 + 0.845 * Atype_C_28-19.493 * The statistical indexes calculated by Shadow_XYfrac are as follows: LOF = 0.291, r2 = 0.766, ra2dj = 0.723, F-test = 17.974, PRESS = 3.469, CV-r2 = 0.791.According to the analysis of the model, The electrophilic and nucleophilic front electron density of -8, the projection of the molecule on the XY plane and the increase of the hydrophobic atom type descriptor Atpye_C_28 are favorable for increasing the affinity between the compound molecule and the receptor. This model reasonably designed two new compounds and predicted higher binding activity.This study provides theoretical guidance for the structural modification of quinoxaline derivatives as human A3 adenosine receptor antagonists and for further study by Body and ligand affinity mechanism laid the theoretical foundation.