Interaction Between FTO Protein And Small Molecule Analogs Investigated By Spectroscopy And Molecular Docking

FTO(fat mass and obesity associated)is the first obesity-related gene.Since the protein expressed by the FTO gene was identified as the first mRNA m~6A demethylase,its biological functions have been widely expanded.In recent years,research has found that FTO not only causes obesity and obesity-related diseases,but also affects the development of hepatitis,various cancers,and acute myeloid leukemia.Therefore,it has become a hot topic to use FTO as a drug target for specific diseases and develop selective inhibitors targeting FTO.The study of the interaction between FTO protein and small molecules,is conducive to guide the design of structure-based targeted FTO drugs.In this dissertation,the interactions of five different types of small molecule analogs with FTO proteins are studied using a variety of spectroscopy methods such as fluorescence analysis,circular dichroism,and molecular docking technique.The main contents of research are as follows:The structure and biological function of FTO protein was briefly reviewed in the first chapter.The methods,contents and significance of this research are summarized.The chapter two studied the interaction mechanisms of FTO and four flavonoids(chrysin,baicalein,daidzein and galangin).The results showed that the fluorescence quenching of FTO by four compounds was mainly static quenching.The order of binding strength was chrysin>baicalein>daidzein>galangin.The chapter three studied the interaction of eight 2H-azirines(1b～1h)with FTO.These 2H-azirines caused static quenching of FTO fluorescence and changed the conformation of FTO.The affinity of 2H-azirines to FTO can be increased by the meta-dichloro substitution(the para-chlorine or para-trifluoromethyl)of benzene ring.The chapter four investigated the interaction between four indolinone analogs and FTO.The results indicated that indolinone derivatives weaken the FTO fluorescence by static quenching,hydrophobic force was the dominant force.Both molecular docking and spectroscopy showed that 2d had the greatest binding capacity to FTO.Chapter five studied the binding of twelve hydrazine derivatives to FTO.Results showed that the fluorescence of FTO was quenched statically by these derivatives,the dynamic quenching mechanism may also exist when 3e,3f binding to FTO.Circular dichroism spectra indicated that twelve hydrazine derivatives reduced theα-helix content of FTO.The position and type of substituents could affect the reaction of hydrazine derivatives with FTO.The interaction of twenty-four 2-imino-1,3,4-oxadiazoline analogues with FTO was studied in chapter six.Results revealed that these analogues were static quenching for FTO.The hydrophobic forces participated in the interaction.Among the compounds studied,the small molecule 4aa with methoxy substitution showed the strongest activity.