Identification of new IDH2R140Q inhibitors by discriminatory analysis-based molecular docking and biological evaluation.
Arch Pharm (Weinheim)
; 354(3): e2000063, 2021 Mar.
Article
en En
| MEDLINE
| ID: mdl-33184958
ABSTRACT
Isocitrate dehydrogenase 2 (IDH2) is a key enzyme in the regulation of cell metabolism. Its mutated type can lead to the accumulation of 2-hydroxyglutarate, which is often related to malignancies such as acute myeloid leukemia. Therefore, it is necessary to find new inhibitors targeting mutant IDH2. Discriminatory analysis-based molecular docking was employed to screen the ChemDiv compound library, which resulted in the identification of three new IDH2R140Q inhibitors with moderate-to-good IC50 values. Among them, compounds 1 and 3 displayed good selectivity against other mutant or wild-type IDH proteins. The most potent compound 1, bearing the [1,2,4]triazolo[1,5-a]pyrimidin scaffold, was subjected to dynamic simulations to provide more information on the binding mode with IDH2R140Q , providing structural clues to further optimize compound 1 as a new mutant IDH2 inhibitor.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Inhibidores Enzimáticos
/
Simulación del Acoplamiento Molecular
/
Isocitrato Deshidrogenasa
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Arch Pharm (Weinheim)
Año:
2021
Tipo del documento:
Article
País de afiliación:
China