| Oxidized purine nucleotides damage repair enzyme MTH1 can keep oxidative purine nucleotides from incorporating into nucleic acids incorrectly.MTH1 plays a key role in the synthesis and replication of DNA and cell proliferation,especially in tumor cells.MTH1 inhibition could prevent the DNA oxidative damage repair,cause the tumor cell proliferative block,and achieve the purpose of tumor therapy.Therefore,MTH1 became the ideal target for the therapy of tumor.The main contents of present work include the design and synthesis of novel MTH1 inhibitors based on MTH1 structure and reported inhibitors.Firstly,the structure and electrical properties of the MTH1 enzyme active cavity will be detected,then MTH1 enzyme inhibitor virtual compound libraries will be build with computer aided drug design(CADD)methods,including fragment growth,fragment connection and scaffold hopping,and so on.Drug-likeness analysis,molecular docking,pharmacophore screening and dynamics simulation will be conducted to screen out valuable compounds.Also reverse virtual screening were progressed on selected molecules,for identifying potential target candidates of selected molecules with pharmacophore mapping approach.Finally an appropriate synthesis route was constructed,also preliminary exploration was conducted,which laid a good foundation for the research and development of MTH1 inhibitors.This project belongs to original research,and its aim is to find new drug candidates or lead compounds for oncotherapy.MTH1 enzyme as a new antitumor target has important scientific and academic value as well as promising application prospect. |
