Structural insights into the Plasmodium falciparum histone deacetylase 1 (PfHDAC-1): A novel target for the development of antimalarial therapy.
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.
Mukherjee
Prasenjit
P
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Pradhan
Anupam
A
Shah
Falgun
F
Tekwani
Babu L
BL
Avery
Mitchell A
MA
D000465:Algorithms; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D011237:Predictive Value of Tests; D013329:Structure-Activity Relationship
D000962:Antimalarials; D004791:Enzyme Inhibitors; D008024:Ligands; D006655:Histone Deacetylases