Inhibitory investigation of niacin derivatives on metalloenzyme indoleamine 2,3-dioxygenase 1 for its immunomodulatory function

文献类型： 外文期刊

第一作者： Yan, Daojing

作者： Yan, Daojing;Tan, Xiangshi;Yan, Daojing;Tan, Xiangshi;Xu, Jiakun

作者机构：

关键词： metalloenzyme; indoleamine 2,3-dioxygenase 1; niacin derivatives; inhibitor; structure-activity relationship

期刊名称：METALLOMICS （ 影响因子：3.796； 五年影响因子：4.176 ）

ISSN： 1756-5901

年卷期： 2021 年 13 卷 3 期

页码：

收录情况： SCI

摘要： Inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) have received wide attention for their roles in cancer immunotherapy. It highlights the important role of metalloenzymes in performing human physiological functions. Herein, the recombinant human IDO1 was expressed and purified successfully, and the protein molecule was characterized by SDS-PAGE, MALDI-TOF mass spectrometry, and metalloenzymology. A series of niacin derivatives were investigated with regard to their inhibition on metalloenzyme IDO1, and the resulting potential anti-cancer activities in cell lines. Among the niacin derivatives, 4,4,4-trifluoro-1-(pyridin-3-yl)-butane-1,3-dione (compound 9) was found to be the most effective inhibitor to IDO1 in HepG-2 cells, with an EC50 of 11 mu M with low cytotoxicity. The IC50 value of compound 9 with trifluoroethyl group in enzymatic inhibition was shown to be similar to 5 times more potent than a positive control 4-phenylimidazole. The interaction between compound 9 and IDO1 was verified by isothermal titration calorimetry and molecular docking study. The most favorable molecular docking results revealed that functional groups of compound 9 contributed to the binding of 9 to IDO1 through IDO1-heme coordination, H-bond interactions and hydrophobic contacts. Our finding provides a strategy for the development of new inhibitor candidates for the therapeutic inhibition of IDO1.

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