Structural insights on identification of potential lead compounds targeting WbpP in Vibrio vulnificus through structure-based approaches.
J Recept Signal Transduct Res
; 36(5): 515-30, 2016 Oct.
Article
en En
| MEDLINE
| ID: mdl-26795501
ABSTRACT
WbpP encoding UDP-GlcNAC C4 epimerase is responsible for the activation of virulence factor in marine pathogen Vibrio vulnificus (V. vulnificus) and it is linked to many aquatic diseases, thus making it a potential therapeutic target. There are few reported compounds that include several natural products and synthetic compounds targeting Vibrio sp, but specific inhibitor targeting WbpP are unavailable. Here, we performed structure-based virtual screening using chemical libraries such as Binding, TOSLab and Maybridge to identify small molecule inhibitors of WbpP with better drug-like properties. Deficient structural information forced to model the structure and the stable protein structure was obtained through 30 ns of MD simulations. Druggability regions are focused for new lead compounds and our screening protocol provides fast docking of entire small molecule library with screening criteria of ADME/Lipinski filter/Docking followed by re-docking of top hits using a method that incorporates both ligand and protein flexibility. Docking conformations of lead molecules interface displays strong H-bond interactions with the key residues Gly101, Ser102, Val195, Tyr165, Arg298, Val209, Ser142, Arg233 and Gln200. Subsequently, the top-ranking compounds were prioritized using the molecular dynamics simulation-based conformation and stability studies. Our study suggests that the proposed compounds may aid as a starting point for the rational design of novel therapeutic agents.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Carbohidrato Epimerasas
/
Vibrio vulnificus
/
Enfermedades Transmitidas por los Alimentos
/
Plomo
Tipo de estudio:
Diagnostic_studies
/
Guideline
/
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Recept Signal Transduct Res
Asunto de la revista:
BIOQUIMICA
/
FISIOLOGIA
Año:
2016
Tipo del documento:
Article