摘要: 禽流感是由甲型流感病毒引起的一类危急人类生命安全的病毒性传染病，由空气传播。本次研究通过使用SYBYL软件，将收集到的46个扎那米韦衍生物，通过实验确定其中的37个分子作为训练集，9个分子作为测试集。将训练集的分子建立了3D-QSAR模型，并用抽一法验证模型的可信度。CoMFA模型的交叉验证系数q2=0.605，最佳主成分数为6，相关系数R2=0.997，标准偏差为0.053，F值为1826.066；CoMISA模型的交叉验证系数q2 =0.691，最佳主成分数为4，相关系数R2=0.993，标准偏差为0.083，F值为1118.743。用测试集的分子对所建模型进行验证，进一步验证模型具有良好的预测能力。然后以CoMFA和CoMISA模型的色块图为依据，活性最高的5号分子作为模版分子，设计了24个新扎那米韦衍生物分子并对新分子进行活性预测。将新分子与准备好的3B7E蛋白进行分子对接，观察最后与受体蛋白的打分值和氢键形成个数。对药物代谢动力学各参数进行分析，选出最优分子。最后，用活性差异较大的8个分子建立GALAHAD药效团模型并对total文件库进行虚拟筛选。71246

毕业论文关键词:　禽流感 ；3D-QSAR；分子对接；计算机辅助药物设计；扎那米韦

The new H1N1 avian influenza virus drug molecules’ 3 D - QSAR study and design

Abstract：Avian influenza is an acute viral respiratory infectious disease caused by influenza A virus, which is seriously harmful to human health and spreads through the air. This study uses SYBYL software，making a raise of 46 zanamivir derivatives. Then through experiments pide them into 37 training molecules and 9 test molecules. Using training molecules to establish 3D-QSAR model, then use the method of Leave-One-Out to validate the model’s reliability. The CoMFA model’s cross validation coefficient q2 =0.605, the best main fraction is 6, the correlation coefficient R2=0.997, the standard deviation is 0.053 and the F=1826.066. The CoMISA model’s cross validation coefficient q2 =0.691, the best main fraction is 4, the correlation coefficient R2=0.993, the standard deviation is 0.083 and the F =1118.743. The model is validated by the test molecules to further validate the model’s good prediction ability. Then based on the CoMFA and CoMISA models’ color lump and conduct the most active molecule No.5 as the template molecule to design 24 new zanamivir derivatives and do activity prediction to them. New molecules dock with the prepared 3B7E protein, then observe the final score value and the formation of hydrogen bond number. Analyzing the pharmacokinetic parameters and choosing the best molecule. Finally, using eight molecules with different activities to establish GALAHAD pharmacophore model for virtual screening of total base.

Keywords: avian influenza; 3D-QSAR; molecular docking; computer aided drug design; zanamivir

目录

1. 前言 1

1.1 研究背景与目的 1

1.2 研究现状与进展 2

1.2.1 N-酰基-1，2，3-三唑扎那米韦衍生物的连接器长度修饰 3

1.2.2 N-酰基-1，2，3-三唑扎那米韦衍生物的修饰 3

1.2.3 酰基胍类扎那米韦衍生物的修饰 4

1.3 研究的基本内容 5

2. 理论原理及计算方法 7

2.1 SYBYL软件 7

2.2 分子对接 7

2.3 三维定量构效关系 7

2.4 比较分子场方法和比较分子相似性指数方法的简介