Mechanism Study And Moleulcar Design Of Targeted Tyrosine Kinases And COX Inhibitors

With the development of science and technology,the research on the therapeutic targets for the disease is becoming more and more clear at molecular level.As the targeted therapy has a significant effect and less side effects,so it has gradually become a trend in the treatment of disease.Because of the long time-consuming and high cost for the traditional drug design,computer-aided drug molecular design(CADD)can effectively reduce the time and cost of targeting inhibitors research,and thus more effectively promote the development of kinase inhibitors.In the part of the introduction,the process of the computer aided drug design was briefly introduced,and how the CADD promotes the development of targeted drugs is described.Second,the targeted tyrosine kinases and cyclooxygenases and their inhibitors are outlined.In Chapter 2,Focal adhesion kinase(FAK)is one kind of tyrosine kinases that regulates integrin and growth factor signaling pathways,which is a promising therapeutic target because of involving in cancer cell migration,proliferation and survival.To investigate the mechanism between FAK and triazinic inhibitors and design high activity inhibitors for FAK,a molecular modeling integrated with3D-QSAR,molecular docking,molecular dynamics simulations and binding free energy calculations was carried out.The optimum CoMFA and CoMSIA modeles showed good reliability and satisfactory predictability(with Q2=0.663,R2=0.987,R2pred=0.921 and Q2=0.670,R2=0.981,R2pred=0.953).Its contour maps could provide structural features to improve inhibitory activities.Furthermore,a good consistency between contour maps,docking and molecular dynamics simulations strong demonstrates that the molecular modeling is reliable.Based on it,we designed several new compounds and their inhibitory activity was validated by the molecular model.We expect our studies could bring new ideas for promoting the development novel inhibitors with higher inhibitory activity for FAK.In Chapter 3,EGFR and HER2 have co-expressed in numerous tumors such as colon,breast,ovarian and prostate cancer,and they are the dual promising therapeutic target.The binding mechanism between dual pyrrolo [3,2-d] pyrimidine inhibitors and EGFR/HER2 was not clearly yet.In this research,we explored the structural insights into the EGFR/HER2 with dual pyrrolo [3,2-d] pyrimidine inhibitors using molecular docking,molecular dynamics simulation,free energy calculation and energy decomposition analysis.Through comparing analyses of the detailed features of EGFR/HER2 with different inhibitors,the dual inhibitors’ common structural features which would contribute to the EGFR/HER2 inhibitory activity is revealed.Furthermore,several dual inhibitors were designed and validated by molecular docking,ADME and toxicity predictions.We hope our research could serve as a paradigm for accelerating the process of developing novel and more promising inhibitors targeting dual EGFR/HER2.In Chapter 4,the cyclooxygenases enzymes(COXs)exist in two isoforms,the constitutive COX1 isozyme and the inducible COX2 isozyme.The constitutive COX1 isozyme is generated in all kinds of tissues and plays vital physiological functions such as gastro protection and vascular homeostasis.Recently,few COX2 specific inhibitors had been developed,but their low selectivity and high toxicity is worthy for us to investigate the COX2 inhibitors with selectivity.We research the binding modes between selectively inhibitors and COXS using molecular docking,molecular dynamics simulation,free energy calculation and energy decomposition analysis.The results showed the key factors of COX2 inhibitors with strong selectivity.The residues Phe504 and Gln178 of COX2 formed hydrogen bonds with inhibitors,so they have stronger polar energy contribution.Since the interval between the residues Ser339/Ser353,Ala502/Ser516 and Val509/Ile523 with inhibitor was different,the non-polar energy contribution of these residues and the contribution of the polar energy of the residues Ile503/Ile517 result in the different selectivity.So this study can provide a direction for designing COX2 inhibitors with high selectivity.