IN inhibitors can be classified into different types，the diketo acid derivates（DKAs）was considered as the most promising inhibitors。 DKAs had active intercellular antiviral activity。 The development of IN inhibitors which based on pharmacophore model of DKAs got rapidly。 The early appeared IN inhibitors including 5-CITEP、S-1360、L-731988、L-708906、L-870810、L-870812，after that，appeared Raltegravir、Elvitegravir、Dolutegravir which were got approved by FDA。

The paper adopted computer-aided drug design method and SYBYL software，based on the previous document experiment to have a design research for DKAs IN inhibitors。 We constructed quantitative structure-activity relationship model between drug and acceptor through three-dimensional quantitative structure-activity relationship（3D-QSAR）。 The model result demonstrated a well predictive ability。 The homologous result about CoMFA in training set was that: cross correlation coefficient q2=0。725，non cross correlation coefficient r2=0。987。 The homologous result about CoMSIA in training set was that: cross correlation coefficient q2=0。564，non cross correlation coefficient r2=0。975。 To analysis force field contour map，we found that added a large volume group at 3，4，5，6 carbon atom of benzyl benzene ring，electropositive group at 4，5 carbon atom of benzyl benzene ring，hydrophobic group at 3，4 carbon atom of benzyl benzene ring，hydrophilic group at 4，5 carbon atom of benzyl benzene ring，IN inhibitory activity was improved。 The paper result can serve as a reference for new IN ibhibitors。

Keywords: HIV-1；Integrase；IN inhibitors；Computer-Aided Drug Design； Three-dimensional Quantitative Structure-activity Relationship

目录

摘要 3

Abstract 4

第一章 绪论 6

1。1 课题背景与研究意义 6

1。1。1 艾滋病的发展现状 6

1。1。2 抗艾滋病药物的现状 6

1。1。3 HIV-1整合酶的结构及作用过程 8

1。2 整合酶抑制剂的分类和研究进展 11

1。2。1第一代整合酶抑制剂 12

1。2。2第二代整合酶抑制剂 14

1。3计算机辅助药物设计（CADD） 15

1。3。1计算机辅助药物设计原理和方法 15

1。3。2计算机辅助药物设计在新药研究中的发展现状 15

第二章 喹啉二酮酸类整合酶抑制剂的三维定量构效关系研究 16

2。1 研究背景与意义 17

2。1。1 定量构效关系（QSAR） 17

2。2 材料和方法 18

2。2。1 数据集的准备 18

2。2。2 化合物分子构建和叠合 19

2。3 结果与讨论 20

2。3。1 模型的统计结果及预测能力 20

2。3。2 CoMFA模型的等势图分析 24

2。3。3 CoMSIA模型的等势图分析 25

2。4 本章小结 28

结论 30

参考文献 31

致谢 37