高等学校化学学报 ›› 2002, Vol. 23 ›› Issue (7): 1304.

• 研究论文 • 上一篇    下一篇

HEPT类逆转录酶抑制剂的三维定量构效关系

孟歌, 何严萍, 陈芬儿   

  1. 复旦大学化学系, 上海 200433
  • 收稿日期:2001-03-27 出版日期:2002-07-24 发布日期:2002-07-24
  • 通讯作者: 陈芬儿(1959年出生),男,博士,教授,博士生导师,从事药物化学研究.E-mail:rfchen@fudan.edu.cn E-mail:rfchen@fudan.edu.cn

Three Dimensional Quantitative Structure-activity Relationship of HEPT Analogues as HIV-1 Reverse Transcriptase Inhibitors

MENG Ge, HE Yan-Ping, CHEN Fen-Er   

  1. Department of Chemistry, Fudan University, Shanghai 200433, China
  • Received:2001-03-27 Online:2002-07-24 Published:2002-07-24

摘要: 利用比较分子力场分析(CoMFA)方法对32个HEPT类HIV-1逆转录酶抑制剂(RTIs)的三维定量构效关系(3D-QSAR)进行了分析,建立了HIV-1逆转录酶抑制剂的3种3D-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-1RT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,CoMFA模型为最佳预测模型,其交叉验证系数RCV2=0.870,传统相关系数R2=0.986,标准偏差SE=0.146,F=294.546.用此模型预测了检验组3个HEPT类化合物的-lgEC50,Rpred2=0.850,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.

关键词: HIV-1逆转录酶抑制剂, HEPT类似物, 比较分子力场分析, 三维定量构效关系

Abstract: Hydroxyethoxy)methyl]-6-(phenylthio)-thymine(HEPT) and its analogues inhibit HIV-1 reverse transcriptase(RT) selectively. Aseries of HEPTanalogues were analyzed in order to disclose the relationship between their structure and the activity. Thirty two HIV-1RTinhibitors were investigated by means of comparative molecular field analysis(CoMFA). Based upon the active conformation extracted from the HEPT/HIV-1RTcomplex, all the inhibitors were aligned and minimized in energy. Three kinds of CoMFAmodels 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 RCV2= 0.870, non-cross-validated R2= 0.986, F =294.546, standard error(SE)=0.146. The CoMFAmodel 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 CoMFAmodel 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.

Key words: HIV-1 reverse transcriptase inhibitors, HEPT analogues, CoMFA, 3D QSAR

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