IOPY/ISPY类HIV-1逆转录酶抑制剂的定量构效关系研究  

Quantitative Structure-Activity Relationship of IOPY/ISPY Analogues as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

作　　者：朱瑞新[1,2] 王飞[2] 刘琦[1] 康廷国[2] 

机构地区：[1]同济大学生命科学与技术学院,上海200092 [2]辽宁中医药大学药学院,沈阳110032

出　　处：《化学学报》2011年第15期1731-1736,共6页Acta Chimica Sinica

基　　金：高等学校博士学科点专项科研基金资助(No.2010-0072120050);国家自然科学基金(No.30976611)资助项目

摘　　要：C-5修饰的3-碘-4-芳氧基/芳硫基吡啶酮(IOPY/ISPY)类化合物是一类潜在的HIV-1非核苷类逆转录酶抑制剂,特别是这类化合物因具有同时抑制野生型和突变型病毒株的特性,而受到更加广泛的关注.首先利用两套2D通用描述符同时构建了该类化合物的线性和非线性定量构效关系模型.结果表明这些模型都具有较好的预测能力,并且非线性模型较线性模型预测能力更好些.为了更好、更形象地描述逆转录酶抑制剂的特征,进一步结合三维定量构效关系(3D-QSAR)模型,以及SAReport分析对该类化合物同时抑制野生型和突变型病毒株的结构特征进行了分析,发现在对这类化合物进行结构修饰时,需要服从如下三条理论指导原则:(1)R基团中的正负电场分布情况对化合物的活性起着关键作用;(2)R基团最好具有芳香环或芳香杂环和(3)R基团的环结构上连接的取代基不宜太多.A series of C-5 modified 3-iodo-4-aryloxypyridinones（IOPY’s） and 3-iodo-4-arylthio-pyridinones（ISPY’s） serves as a potential class of HIV-1 non-nucleoside reverse transcriptase inhibitors.These two pyridinone analogues are attracting more attentions mainly due to their potential abilities to si-multaneously inhibit wild type and mutant HIV-1 strains.In this study,two sets of traditional two-dimensional descriptors were applied respectively to create linear and binary QSAR models for these compounds.Our results indicated the well prediction ability of the obtained models.It is also indicated that binary model achieved a better prediction results than the linear one.Furthermore,in order to obtain a better description of the structure characteristics of the HIV-1 reverse transcriptase inhibitors,3D-QSAR models and SAReport analysis were used to explore the compound features which contribute to the inhibition of wild type as well as mutant HIV-1 strains.Our analysis reveals that there may existed three principles to follow when the compounds are modified：（i） the electrostatic potentials distribution of R-groups plays a key role in determining the biological activities of the compounds;（ii） an aromatic ring or aromatic heterocycle for R-groups is favorable to enhance the biological activity;and finally（iii） the number of substituents attached to the ring of R-groups should be appropriate.

关 键 词：定量构效关系 非核苷类逆转录酶抑制剂 HIV-1 吡啶酮衍生物 

分 类 号：R914[医药卫生—药物化学]