Calorimetry And Spectroscopy Studied On The Interaction Between FTO Protein With Small Molecule Analogs

The fat mass and obesity associated(FTO)is a gene related to obesity,and it may influence the expression of other genes through demethylation.It is not clear whether the FTO protein is an effective drug target now,but the interaction between small drug molecule and protein can predict the development process of the drug action to some extent.Therefore,study on the interaction between small molecular and FTO protein can help screen the FTO inhibitors and guide the design and optimization of lead compounds.This paper combined calorimetry and spectroscopy to study the interaction of small molecules(carbazole alkaloids,nucleoside analogues,camptothecin and its analogs,three nitrogen thiazole derivatives)and FTO protein.The main contents of research are as follows:The chapter one mainly introduced the structure and function of the protein,the research methods,the main contents and significance of the interaction between small molecule and FTO protein.The chapter two united calorimetry,spectroscopy and molecular simulation technology to study the interaction of FTO protein and six carbazole alkaloids compounds(2a~2f).Results showed that only compound 2e could binding to FTO protein,and the process was static quenching.Hydrogen bond and hydrophobic force played the major role in the interaction between FTO protein and compound 2e.The conformation of FTO protein changed in the experiment.The chapter three studied the interaction of six nucleoside analogs compounds(3a~3f)and FTO.Results indicated that the six nucleoside analogs compounds quenched the fluorescence of FTO through static quenching mechanism,and hydrophobic interaction played a primary role in the binding process.The stability of the complex increased with increasing temperature,and compound 3d was the strongest quencher.The chapter four investigated the interaction between FTO protein with three kinds of camptothecin and its analogs(4a~4c).The quenching mechanism of camptothecin and its analogs with FTO protein was static quenching,and electrostatic force and hydrophobic force played the major role in these systems.The types and positions of substituents would affect the reaction results.The quenching ability of 4b was greater than other two compounds.The chapter five investigated the interaction between FTO protein and six kind of three nitrogen thiazole derivatives(5a~5f),the quenching mechanism of six compounds with FTO protein was static quenching.Hydrophobic interactions acted a primary role in the binding process,and 5a~5f can cause the change of FTO protein conformation and the microenvironment around the internal amino acid residues.The quenching ability and affinity of compound 5a and 5f were greater than other analogs,and compound 5c was the least.Molecular simulation results were consistent with the spectroscopy.