Identification of a natural product-like STAT3 dimerization inhibitor by structure-based virtual screening.
Cell Death Dis
; 5: e1293, 2014 Jun 12.
Article
em En
| MEDLINE
| ID: mdl-24922077
ABSTRACT
STAT3 regulates a variety of genes involved with cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, inflammation, and immunity. The purpose of this study was to apply molecular docking techniques to identify STAT3 inhibitors from a database of over 90000 natural product and natural product-like compounds. The virtual screening campaign furnished 14 hit compounds, from which compound 1 emerged as a top candidate. Compound 1 inhibited STAT3 DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with selectivity over STAT1 and with comparable potency to the well-known STAT3 inhibitor S3I-201. Furthermore, compound 1 inhibited STAT3 dimerization and decreased STAT3 phosphorylation in cells without affecting STAT1 dimerization and phosphorylation. Compound 1 also exhibited selective anti-proliferative activity against cancer cells over normal cells in vitro. Molecular docking analysis suggested that compound 1 might putatively function as an inhibitor of STAT3 dimerization by binding to the SH2 domain. This study also validates the use of in silico techniques to identify inhibitors of protein-protein interactions, which are typically considered difficult to target with small molecules.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Transcrição STAT3
/
Multimerização Proteica
/
Simulação de Acoplamento Molecular
/
Antineoplásicos
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article