Study On Quantitative Structure-activity Relationship And Virtual Screening Of Type Ⅰ C-Met Kinase Inhibitors

According to WHO,about 9 million people died of cancer in a year,the equivalent of 22,000 deaths from cancer every day,which will hinder people’s lives and longer life.As a member of tyrosine kinase receptor,mesenchymal-epithelial transition factor（c-Met）is an important factor in the process of intervention and treatment of cancer.Hepatocyte growth factor（HGF）is the only known c-Met endogenous ligand.c-Met/HGF signaling pathway is associated with the occurrence of many cancers（mainly lung cancer）,and also is associated with many other cellular signaling pathways.Therefore,the study of small molecule inhibitors targeting c-Met kinase has become an important direction and hot spot in the current field of anticancer drug research.In the first part of this thesis,we presented cancer briefly,including the current development of cancer and treatment.Additionally,the structure and function of c-Met kinase and HGF were introduced.Then we introduced the information of the c-Met/HGF signaling pathway,drug resistance mechanism and the classification of c-Met kinase small molecule inhibitors.Finally,the significance and goals of this topic were introduced.In the second part,we presented the computer-aided drug design related to the thesis,including principles and methods briefly,such as two-dimensional quantitative structure-activity relationship（2D-QSAR）,three-dimensional quantitative structure-activity relationship（3D-QSAR）,Topomer Co MFA was used to analyze 3D images based on fragments-QSAR modeling technology,3D ligand virtual screening Topomer Search,molecular docking,virtual screening and other technologies.In chapter 3,chapter 4 and chapter 5,the 2-aminopyridine,pyridazinone and 1-sulfonylpyrazolo[4,3-b]pyridine type I c-Met inhibitors were studied respectively.2D-QSAR model was constructed based on MLR,3D-QSAR models（Co MFA,Topomer Co MFA and Co MSIA）were established to study the quantitative relationship between the two types of c-Met typeⅠc-Met small molecule inhibitors and structural characteristics related to the corresponding inhibitory activities,we can identify key structural features that affect activity,so as to provide a theoretical basis for the structural modification of compounds.The sixth chapter of the thesis is designing and screening of new c-Met inhibitors.based on the aforementioned three types c-Met small molecule inhibitors,using Topomer Search technology cut the most active small molecules into two fragments,Ra and Rb,Ra contained the scaffold as a question type to screen the drug lead-like compounds in the ZINC database,we used the established Co MFA and Co MSIA models to predict the theoretical activity of the screened compounds.The compounds with p IC₅₀>6 were retained for drug lead like screening and ADME screening.The aforementioned compounds were docked with c-Met kinase（PDB ID:3CCN）and clustered using Libdock,Glide XP.Finally,45 compounds were found to be potential c-Met kinase inhibitors.This paper applied computer-aided drug design methods to establish quantitative structure-activity relationship model for three type I c-Met inhibitors,we revealed the inhibitors that were highly correlated with biological activity structural features,and used for virtual screening of new c-Met inhibitors.This provides a theoretical basis for the discovery of novel c-Met small molecule inhibitors.