Virtual Screening And Molecular Dynamics Study Of Src And Abl Single And Double Target Inhibitors

Both Src and Abl belong to non-receptor tyrosine kinases,which all play important roles in regulating signal transduction,and when they are the overexpression of Src may lead to the proliferation and differentiation of the cells and then cause the cells to become cancerous.Therefore,specifically blocking the Src-and Abl-mediated signal transduction can effectively treat cancer,and thus Src and Abl kinases have become effective targets for cancer therapy.Meanwhile,the differentiation process of tumor cells is complicated and the signals are interlaced.Dualor multi-target inhibitors can simultaneously act on multiple molecular targets of cancer,which not only can treat cancer more effectively,but also effectively overcome the drug resistance.In recent years,the studies of the dual-or multi-target inhibitors have become a hot spot in the current international anticancer agents research.Hence,on the basis of previous studies of the action mechanisms,virtual screening of Src,Abl and Src/Abl lead candidates is very significant for designing and optimizing novel structural skeleton inhibitors.This dissertation includes the following five chapters.In the first chapter,the structural characteristics and functions of Src Abl kinases are briefly reviewed.The research significance and progress of Src,Abl and Src/Abl inhibitors were systematically summarized.Meanwhile,the common methods and related softwares of computer-aided drug design as well as the significance of this study were also briefly introduced.In the second chapter,the ligand-based and receptor-based pharmacophore models were constructed by selecting the known Src inhibitors and Src crystal structure,respectively.The test set and decoy set compounds as well as the fischer’s randomization test methods were used to evaluated the generated pharmacophore model to find the optimal one which was used for the virtual screening of the compound databases.The preliminary screening compounds were subjected to drug-like,molecular docking,pharmacokinetics and toxicology screening and eight preferred compounds were gained.Finally,the detailed binding modes of these candidates was verified by molecular dynamics simulation and binding free energy analysis.In the thrid chapter,we discussed detailed progress to generate the ligand-based and receptor-based pharmacophore models and verifed using different methods.Then,a virtual screening strategy including pharmacophore models,molecular docking,pharmacokinetics and toxicology filters werechosen to identify potential lead candidates from huge compound databases.Five different compounds were obtained.Finally,molecular dynamics simulation and binding free energy analysis were used to explore the binding modes of these compounds.In the fourth chapter,we analyzed the structures and activities of Src/Abl dual inhibitors reported from the literatures,a pharmacophore model based on the common features of ligands was constructed.The validated pharmacophore were used for screening of the database,and the compounds matching the pharmacophore will be further screened by drug-like,molecular docking,pharmacokinetics and toxicology properties.Then,three preferred compounds were received.Finally,the binding modes of the compounds to the receptors were obtained and evaluated by molecular dynamics simulation and binding free energy analysis.In the fifth chapter,the summary and prospect were presented for this work.