Download MendeleyRepositioning Food and Drug Administration-Approved Drugs for Inhibiting Biliverdin IX beta Reductase B as a Novel Thrombocytopenia Therapeutic Target.
Kim, M., Ha, J.H., Choi, J., Kim, B.R., Gapsys, V., Lee, K.O., Jee, J.G., Chakrabarti, K.S., de Groot, B.L., Griesinger, C., Ryu, K.S., Lee, D.(2022) J Med Chem 65: 2548-2557
- PubMed: 34957824
- DOI: https://doi.org/10.1021/acs.jmedchem.1c01664
- Primary Citation of Related Structures:
7ER6, 7ER7, 7ER8, 7ER9, 7ERA, 7ERB, 7ERC, 7ERD, 7ERE - PubMed Abstract:
Biliverdin IXβ 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 IC 50 (<5 μM), 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 (Δ H , Δ 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.
Organizational Affiliation:
Protein Structure Research Team, Korea Basic Science Institute, 162 Yeongudanji-Ro, Ochang-Eup, Cheongju-Si, Chungcheongbuk-Do 28119, South Korea.
