【摘要】 利用比较分子力场分析 (Co MFA)方法对 3 2个 HEPT类 HIV-1逆转录酶抑制剂 (RTIs)的三维定量构效关系 (3 D-QSAR)进行了分析 ,建立了 HIV-1逆转录酶抑制剂的 3种 3 D-QSAR模型 ,发现影响其生物活性的主要因素为立体场因素 ,这与 HIV-1 RT的非底物结合部位 (NNBS)的疏水性环境相吻合 .进一步分析表明 ,适当长度的 1 -位侧链对保持化合物的抗病毒活性致关重要 ;增大 5 -位取代基的体积可增强生物活性 ;在 1 -位苄氧甲基的对位引入大体积基团有利于提高活性 .同时考察立体场、静电场与生物活性的关系 ,表明 ,Co MFA模型 为最佳预测模型 ,其交叉验证系数 R2CV=0 .870 ,传统相关系数 R2 =0 .986,标准偏差SE=0 .1 46,F =2 94.5 46.用此模型预测了检验组 3个 HEPT类化合物的 -lg EC50 ,R2pred=0 .85 0 ,表明模型具有很好的预测能力 ,可为 HEPT类 HIV-1逆转录酶抑制剂的结构优化提供理论指导 .更多还原

【Abstract】 Hydroxyethoxy)methyl] 6 (phenylthio) thymine(HEPT) and its analogues inhibit HIV 1 reverse transcriptase(RT) selectively. A series of HEPT analogues were analyzed in order to disclose the relationship between their structure and the activity. Thirty two HIV 1RT inhibitors were investigated by means of comparative molecular field analysis(CoMFA) . Based upon the active conformation extracted from the HEPT/HIV 1RT complex, all the inhibitors were aligned and minimized in energy. Three kinds of CoMFA models were established and evaluated. The model(Ⅰ)of steric and electrostatic effects on their activities showed a higher ability to explain and predict the activities of these selective HIV 1 inhibitors than other models, cross validated R 2 CV = 0.870 , non cross validated R 2= 0.986 , F =294 546, standard error(SE)=0.146. The CoMFA model established by examining the steric and electrostatic effect on the structure without considering the effect of π value shows a very high ability to predict the biological activity for testing set compounds and training set compounds and offers an approach to design the new inhibitors. The CoMFA model revealed that the suitable length of the 1 side chain is crucial for the antiviral activity. And it also showed that the bulkier group in 5 position and the para position of the 6 phenylthio group is also benefit for the enhancement of the antiviral activity.更多还原