Quantitative Structure Activity Relationship Study On Neuraminidase Inhibitor And Synthesis Of Pyrimidines

The negligence of the drug, which used on influenza, caused a global shortage of it. There are only two kinds of major drugs of influenza on the market. At the same time, the fear of avian flu has led to the governments to take corresponding measures of drug storage with a result of the demand of influenza's drug became more and more intense. However, it also has brought about a positive outcome with the research of influenza's drug started to resuscitate. Since the 1983, when the crystal structures of influenza virus neuraminidase(NA) and it with its natural substrate of sialic acid have been determined, researches of neuraminidase inhibitors particular its sialic acid analogues for influenza virus has been obtained great progress. Understanding of the crystal structure allows people to do the research of molecular simulations and then to design inhibitors with high efficiency and selectivity. Moreover quantitative structure activity relationship (QSAR) study is an important method of drug design and it has important significance to design and development of high efficiency anti-influenza drug and construction of these compounds'mechanism between the molecular structure and biological activity.In this paper, we summarize the progress in influenza virus NA inhibitors and QSAR methods. Using 2-D-QSAR and 3-D-QSAR technology, the influenza virus NA inhibitors are studied in the aspect of QSAR and computer aided drug design are actualized. The synthesis and analysis of partial target molecules are accomplished aiming at getting new molecule structures of influenza's drug. The main content and achievement of this thesis are followed:1. The molecular descriptors molecular electronegativity-distance vector (MEDV)and three dimensional holographic vector of atomic interaction field (3D-HoVAIF) are used to structural characterization for a couple of sample systems of NA inhibitor and the quantitative relationship models have been constructed by using stepwise multiple regression (SMR) and multiple linear regression(MLR)technique. The models constructed with 3D-HoVAIF are better in estimated properties and predictive abilities than that of MEDV. The results primarily show that description of the MEDV is not applicable to characterizing of the structure of neuraminidase inhibitors compared with 3D- HoVAIF.2. The molecular descriptors 3D-HoVAIF is used to describe the structures of 40 kinds of NA inhibitors of pyrimidines and the anther QSAR model with five variables is obtained through SMR and MLR. The modeling results are R=0.923,SD=1.146,R~2CV=0.679 ,SDCV=1.513. It is indicated that the estimated property and predictive ability are satisfactory. And it is also illuminated that 3D- HoVAIF can be used to well express the information of these organic compounds'structures and is applicable to characterizing of the structure of neuraminidase inhibitors.3. In order to analysis the expression ability and modeling capability of 3D- HoVAIF for NA inhibitors thoroughly. 123 samples of NA inhibitor containing heterocyclic nitrogen compound are divided into two parts, namely, training set and test set for the 100 and 23 samples. And the quantitative relationship models have been constructed by using MLR and partial least squares(PLS) technique. Results: The correlation coefficient (R2), cross-validation of the correlation coefficient (Q2) and the root mean square error model for R2 = 0.705, Q2 = 0.657, RMS = 0.936, respectively. The model has a good stability and predictability and the 23 drugs in the literature and 36 designed compounds were predicted. That three-dimensional holographic atomic field vector can better characterizing of the molecular structure and it should be further popularized.4. Among the predicted activity values of 36 designed compounds, the pyramid- ines and cyclohexenes exhibit upper bioactivity. So six derivatives of pyrimidine are selected including 2-mercapto-6-methylpyrimidin-4-ol, 6-methylpyrimidine-2,4-diol, 2-methoxy-6-methylpyrimidine-4-ol, 2,6-dihydroxypyrimidine-4-carboxylic acid, 6- hydroxy-2-methoxypyrimidine-4-carboxylic acid and 2-ethoxy-6-hydroxypyrimid- ine-4-carboxylic acid. The synthesis, purification and structure analysis of these compounds are carried out in laboratory. And the synthesis technics of 2-methoxy-6- methylpyrimidine-4-ol is optimized. And it is may be significant for the next activity test and medicament filter.