Valproic acid as a potential inhibitor of Plasmodium falciparum histone deacetylase 1 (PfHDAC1): an in silico approach.
Int J Mol Sci
; 16(2): 3915-31, 2015 Feb 11.
Article
em En
| MEDLINE
| ID: mdl-25679451
ABSTRACT
A new Plasmodium falciparum histone deacetylase1 (PfHDAC1) homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations were acceptable and consistent. Docking a group of hydroxamic acid histone deacetylase inhibitors and valproic acid has shown binding poses that agree well with inhibitor-bound histone deacetylase-solved structural interactions. Docking affinity dG scores were in agreement with available experimental binding affinities. Further, enzyme-ligand complex stability and reliability were investigated by running 5-nanosecond molecular dynamics simulations. Thorough analysis of the simulation trajectories has shown that enzyme-ligand complexes were stable during the simulation period. Interestingly, the calculated theoretical binding energies of the docked hydroxamic acid inhibitors have shown that the model can discriminate between strong and weaker inhibitors and agrees well with the experimental affinities reported in the literature. The model and the docking methodology can be used in screening virtual libraries for PfHDAC1 inhibitors, since the docking scores have ranked ligands in accordance with experimental binding affinities. Valproic acid calculated theoretical binding energy suggests that it may inhibit PfHDAC1.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
/
Ácido Valproico
/
Histona Desacetilase 1
/
Inibidores de Histona Desacetilases
/
Antimaláricos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Int J Mol Sci
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Sudão