Repositioning Food and Drug Administration-Approved Drugs for Inhibiting Biliverdin IXß Reductase B as a Novel Thrombocytopenia Therapeutic Target.
J Med Chem
; 65(3): 2548-2557, 2022 02 10.
Article
em En
| MEDLINE
| ID: mdl-34957824
ABSTRACT
Biliverdin IXß 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 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 (ΔH, ΔS, and KD) 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oxirredutases atuantes sobre Doadores de Grupo CH-CH
/
Inibidores Enzimáticos
/
Bibliotecas de Moléculas Pequenas
Limite:
Humans
País como assunto:
America do norte
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article