The Computer Aid Molecular Design Research On Two Inhibitors

The thesis is about cyclin—dependent—kinases 4 (CDK4) and cytochrome bc₁ complex. Homology modeling method , molecular docking and quantitive structure — activity relationshitp (QSAR)had been applied. There are two main parts, as follows:In the first part, the researches based on cyclin—dependent—kinases 4(CDK4) and inhibitors had been applied. Firstly, Using cyclin—dependent—kinases 2 (CDK2) as a structural template, the 3D structure of CDK4 was built with homology modeling method. Rational analysis of the modeled structure was performed. Subsequently, eight known inhibitors were selected for docking study. The result shows that there exists a good correlation between the calculated binding energy and the inhibitory activity with the conventional correlation coefficient (r²) being 0.79. While, different docking patterns had been researched, some rational explanations were provided for the different activities of these inhibitors. Secondly, Classic 2D-QSAR method was applied to the studies of the relationship of CDK4 inhibitors and their inhibitive activity. Satisfying results were obtained with cross-validation coefficient (q²) and linear correlation coefficient (r²) equal to 0.66 and 0.85 for HQSAR. These models will be used to provide theoretical foundation for synthesizing new CDK4 inhibitors. Thirdly, the CDK4 inhibitors were studied by the quantitative structure-activity relationship (CoMFA) . It was found that the results of CoMFA is good, cross-validation coefficient (q²) and linear correlation coefficient (r²) equal to 0.76 and 0.95. In order to test the model, ten inhibitors with certain experimental inhibitory activity value were selected to calculate, the result shows that there exists a good correlation between the calculated inhibitory activity value and the experimental inhibitory activity value with the conventional correlation coefficient (r²) being0.89.These results all indicates that the model is successful. Based on the model, 25 inhibitors without certain experimental inhibitory activity value were selected to predict. The predicted result was satisfying.In the second part, 8 inhibitors, which belong to the strobilurin (or the melithiazol) class of fungicides, were selected for docking by application of dock 4.0 program. The result shows that there exists a good correlation between the calculated binding energy and the inhibitory activity with the conventional correlation coefficient (r2) being 0.75. Different docking patterns had been researched, some rational explanations were provided for the different activities of these inhibitors. Particularly, four new compounds with potentially high activity had been put forward based on the docking result. The model will provide useful information for designing new inhibitors of cytochrome bci complex.