Discovery of novel DNA methyltransferase 3A inhibitors via structure-based virtual screening and biological assays.
Bioorg Med Chem Lett
; 27(2): 342-346, 2017 01 15.
Article
em En
| MEDLINE
| ID: mdl-27899265
ABSTRACT
DNA methyltransferases are involved in diverse biological processes and abnormal methylation patterns play essential roles in cancer initiation and progression. DNA methyltransferase 3A (DNMT3A) acting as a de novo DNA methyltransferase, has gained widespread attention especially in haematological diseases. To date, large numbers of DNMTs inhibitors have been discovered, however, the small molecular inhibitors targeting DNMT3A are still in its infancy. In this study, structure-based virtual screening in combination with biological assays was performed to discovery potent novel DNMT3A inhibitors. Compound 40 and 40_3 displayed comparable in vitro inhibitory activity against DNMT3A with IC50 values of 46.5µM and 41µM, respectively. Further binding mode analysis suggested these molecules inhibit DNMT3A activity through binding the S-adenosyl-l-methionine (SAM) pocket. Overall, 40 and 40_3 may serve as novel scaffolds for further optimization and small molecular probes for investigating DNMT3A function.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA (Citosina-5-)-Metiltransferases
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Inibidores Enzimáticos
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Descoberta de Drogas
Tipo de estudo:
Diagnostic_studies
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Screening_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article