非核苷类HIV-1逆转录酶抑制剂Ⅱ6-(1-萘甲基)胸腺嘧啶类化合物三维定量构效关系

Nonnucleoside HIV-1 reverse transcriptase inhibitors I 3D-QSAR study on 6-(1-naphthylmethyl)substituted thymines

目的进一步研究6-(1-萘甲基)取代胸腺嘧啶类(HEPT)HIV-1逆转录酶抑制剂的构效关系。方法利用比较分子力场分析方法(CoMFA)对14个新合成的6-(1-萘甲基)取代HEPT类似物进行三维定量构效关系研究;对化合物与HIV-1逆转录酶的非底物结合部分(NNBP)作用情况进行了对接(Dock)研究;并建立了回归方程。结果用模型预测了2个6-(1-萘甲基)取代HEPT类化合物的-logEC50值,结果得以验证。空间立体效应占85.7％,静电立场效应占14.3％。结论对接结果显示:在NNBP中,化合物以蝴蝶双翅形的构象伸展开来,并以芳环与结合腔表面的芳香性氨基酸残基产生疏水性相互作用。6-位引入(1-萘甲基)可显著提高化合物的生物活性,空间效应是影响活性的主要因素,此模型可为进一步的结构优化提供理论指导。

Aim To evaluate the quantitative structure and activity relationship of a series of new 6-naphthyl-methyl substituted HEPT analogs. Methods These new compounds were designed and synthesized for the e-valuation of biological anti-HIV-1 activity. The data were investigated and analyzed by using the Comparative Molecular Field Analysis(CoMFA)method, selecting 14 compounds as the training set and 2 compounds as the testing set. Some docking analyses were also used to draw the final conclusion. Result A reasonable model with considerable predictive ability was obtained. Cross-validated R2CV = 0.539, non-cross-validated R2 = 0.975, F = 88.702, standard error SE = 0.170. The result of 3D-QSAR indicated that the variation in the activity among the 14 title compounds was dominated mainly by differences in the steric effect but the electrostatic effect was also quite important. Conclusion The introduction of the 1-naphthylene group would benefit the enhancement of the anti-HIV-1 activity. This 3D-QSAR model and docking analysis offered an approach to designing the new inhibitors against HIV-1 RT.