Structural insights into the Plasmodium falciparum histone deacetylase 1 (PfHDAC-1): A novel target for the development of antimalarial therapy.
Bioorg Med Chem
; 16(9): 5254-65, 2008 May 01.
Article
em En
| MEDLINE
| ID: mdl-18362073
ABSTRACT
The histone deacetylase (HDAC) enzyme from Plasmodium falciparum has been identified as a novel target for the development of antimalarial therapy. A ligand-refined homology model of PfHDAC-1 was generated from the crystal structures of human HDAC8 and HDLP using a restraint guided optimization procedure involving the OPLS/GBSA potential setup. The model was extensively validated using protein structure checking tools. A predictive docking study was carried out using a set of known human HDAC inhibitors, which were shown to have in vitro antimalarial activity against the chloroquine sensitive D6 and resistant W2 strains of P. falciparum. Pose validation and score-based active/inactive separation studies provided independent validation of the geometric accuracy and the predictive ability of the generated model. Comparative analysis was carried out with the human HDACs to identify differences in the binding site topology and interacting residues, which might be utilized to develop selective PfHDAC-1 inhibitors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
/
Inibidores Enzimáticos
/
Histona Desacetilases
/
Antimaláricos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article