Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking and Dynamics.
Biomolecules
; 8(3)2018 07 23.
Article
em En
| MEDLINE
| ID: mdl-30041464
Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative, and antineoplastic activities. Recently, different studies showed that flavonoids have the potential to inhibit bromodomain and extraterminal (BET) bromodomains. Previous reports suggested that flavonoids bind between the Z and A loops of the bromodomain (ZA channel) due to their orientation and interactions with P86, V87, L92, L94, and N140. Herein, a comprehensive characterization of the binding modes of fisetin and the biflavonoid, amentoflavone, is discussed. To this end, both compounds were docked with BET bromodomain 4 (BRD4) using four docking programs. The results were post-processed with proteinâ»ligand interaction fingerprints. To gain further insight into the binding mode of the two natural products, the docking results were further analyzed with molecular dynamics simulations. The results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was experimentally tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as the basis for scaffold optimization and the further characterization of flavonoids as BET inhibitors.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Biflavonoides
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Biomolecules
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
México
País de publicação:
Suíça