基于分子对接的6-萘甲基取代HEPT类HIV-1逆转录酶抑制剂构效关系研究  

Structure-activity Relationship Studies on 6-Naphthylmethyl Substituted HEPT Derivatives as Non-nucleoside Reverse Transcriptase Inhibitors Based on Molecular Docking

作　　者：何严萍[1] 胡海荣[1] 许辽萨[1] 孟歌[1] 范康年[1] 陈芬儿[1] 

机构地区：[1]复旦大学化学系,上海200433

出　　处：《高等学校化学学报》2005年第2期254-258,共5页Chemical Journal of Chinese Universities

基　　金：国家自然科学基金 (批准号 :2 0 10 3 0 0 2 )资助

摘　　要：采用分子对接方法得到了一系列 6-萘甲基取代 HEPT类逆转录酶抑制剂分子与 HIV-1逆转录酶复合物模型 ,从中抽取出抑制剂分子的活性构象 ,进一步应用 Co MFA和 Co MSIA方法建立了具有较好预测能力的 3 D-QSAR模型 ,深入探讨了这些化合物的定量构效关系 ,为进一步的药物设计奠定了良好的基础 .另外 ,以化合物 1 3及其相应的 β异构体 2 4为代表 ,结合量子化学从头算分子轨道理论方法考察了它们的前线轨道 ,为阐明 α和 β系列化合物的活性差异提供了理论依据 .The research on 1-[(2-hydroxyethoxy)methyl]6-(phenylthio)thymine(HEPT), as one of the most important reverse transcriptase(RT) inhibitors against human immunodeficiency virus(HIV), remains a hot issue these years. The complex models of a series of 6-napthylmethyl substituted HEPT analogues with HIV-1 RT have been obtained by employing molecular docking approach. Using the binding conformations of these HEPT analogues, self-consistent and highly predictive 3D-QSAR models have been developed by performing CoMFA and CoMSIA analysis, which further guide the design of new candidates in return. Mapping these models back to the topology of the active site of HIV-1 RT led to a better understanding of the vital inhibitor-HIV-1 RT interactions. Taking compound 13 and its β-isomer 24 as the representatives, the reasons for the activity difference of α- and β-series analogues were presented by employing ab initio molecular orbital theoretical method. The best resulting CoMFA and CoMSIA models had conventional r2 values of 0.997 and 0.994, while their leave-one-out cross-validated q2 values were 0.787 and 0.747, respectively, suggesting a good predictive ability of these two models. Our research results also suggested that CoMSIA model was somewhat equivalent to the COMFA one. These models offer insight into the structural requirements for the activity of HEPT analogues as promising inhibitors, since there is only speculative knowledge of the target.

关 键 词：键词HIV-1逆转录酶抑制剂 HEPT类似物 分子对接 比较分子力场分析(CoMFA) 比较分子相似因 子分析(CoMSIA) 量子化学从头算 

分 类 号：O626[理学—有机化学] R914[理学—化学]