QSAR And Molecular Docking Studies On HIV-1 NNRTIs,c-Met And Thrombin Inhibitors

AIDS, cancer, and cardiovascular disease have a higher human incidence and mortality rates, as a serious threaten to human life and health. The study of AIDS, cancer and cardiovascular disease drugs become a current event in the world. Wherein, HIV-1 reverse transcriptase, c-Met kinase and direct thrombin (Thrombin) are the key target protease of these three diseases, respectively. The corresponding kinase inhibitors are the key treatment of such diseases. In recent years, with the development of computer technology, the computer aided drug design method has been widely used in the process of drug design.In this thesis, HIV-1 reverse transcriptase inhibitors, c-Met kinase inhibitors and direct thrombin inhibitors were studied using a combination of molecular modeling technology including three-dimensional quantitative structure activity relationship (3D-QSAR) and molecular docking simulation according to the molecular structure. We established the 3D-QSAR models of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) enzyme inhibitory activity, triazolo[4,5-b]pyrazine derivatives and the thrombin inhibitors, respectively. The optimal correlation between the results of comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) models are:q2= 0.636, r2= 0.993 and q2= 0.655, r2= 0.998; q2= 0.622, r2= 0.956 and q2= 0.720, r2= 0.987; q2= 0.709, r2= 0.992 and q2= 0.618, r2= 0.992. According to the contour map analyses of five force fileds, the corresponding position of cyclopentyl and pyrimidine ring of the HIV-1 reverse transcriptase inhibitors introduced the large and electropositive groups could improve the inhibitory activity; the position of quinoline and pyrazole ring of the c-Met inhibitors introduced the large and electronegative groups could improve the inhibitory activity, respectively; the position of benzimidazole and pyrimidine ring introduced a large electropositive groups could improve the anticoagulant activity. Furthermore, molecular docking was used to study the three mechanism of small molecule inhibitors with their target proteins, we found a series of amino acid residues whose play an important role in hydrogen bonding and hydrophobic interactions with the target protein. Finally, molecular docking, QSAR model prediction and synthetic work were used to evaluate the accuracy of the established models. Experimental results show that the model has good stability and predictability. The conclusions can provide theoretical guidance for the design and synthesis of newly HIV-1, c-Met and thrombin inhibitors.