Identification of 5-benzylidene-2-phenylthiazolones as potent PRMT5 inhibitors by virtual screening, structural optimization and biological evaluations.
Bioorg Chem
; 81: 289-298, 2018 12.
Article
en En
| MEDLINE
| ID: mdl-30172110
ABSTRACT
Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for glioblastoma and mantel cell lymphoma. In the present study, 11 novel PRMT5 inhibitors with 5-benzylidene-2-phenylthiazolone scaffold were identified by molecular docking-based virtual screening and structural optimization. Their IC50 values against PRMT5 at enzymatic level were ranging from 0.77 to 23⯵M. As expected, the top two active hits (5 and 19) showed potent anti-proliferative activity against MV4-11 cells with EC50 values lower than 10⯵M and reduced the cellular symmetric arginine dimethylation levels of SmD3 protein. Besides, 5 and 19 demonstrated the mechanism of cell killing in cell cycle arrest and apoptotic effect. The probable binding modes of the two compounds were explored and further verified by molecular dynamics simulation. The structure-activity relationship (SAR) of this class of structures was also discussed and further demonstrated by molecular docking simulation.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteína-Arginina N-Metiltransferasas
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Tiazoles
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Compuestos de Bencilideno
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Bases de Datos de Compuestos Químicos
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Antineoplásicos
Tipo de estudio:
Diagnostic_studies
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Screening_studies
Límite:
Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article