期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 3, 页码 2548-2557出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01664
关键词
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资金
- KBSI internal research programs [T39632, C030130, C140130, C130000]
- James Graham Brown Cancer Center
This study focuses on Biliverdin IX beta reductase B (BLVRB) as a novel therapeutic target for thrombocytopenia, with the goal of repurposing drugs as new inhibitors of BLVRB. Through screening a library of FDA-approved compounds, 20 potential compounds were identified with high binding affinity to BLVRB's active site. The detailed binding modes, thermodynamic properties, and complex structures of water-soluble compounds provide a foundation for further research on the effects of BLVRB on ROS accumulation and megakaryocyte differentiation, potentially leading to new treatments for platelet disorders.
Biliverdin IX beta reductase B (BLVRB) has recently been proposed as a novel therapeutic target for thrombocytopenia through its reactive oxygen species (ROS)-associated mechanism. Thus, we aim at repurposing drugs as new inhibitors of BLVRB. Based on IC50 (<5 mu M), we have identified 20 compounds out of 1496 compounds from the Food and Drug Administration (FDA)-approved library and have clearly mapped their binding sites to the active site. Furthermore, we show the detailed BLVRB-binding modes and thermodynamic properties (Delta H, Delta S, and K-D) with nuclear magnetic resonance (NMR) and isothermal titration calorimetry together with complex structures of eight water-soluble compounds. We anticipate that the results will serve as a novel platform for further in-depth studies on BLVRB effects for related functions such as ROS accumulation and megakaryocyte differentiation, and ultimately treatments of platelet disorders.
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