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Structural insights into the Plasmodium falciparum histone deacetylase 1 (PfHDAC-1): A novel target for the development of antimalarial therapy |
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| Authors: | Mukherjee Prasenjit Pradhan Anupam Shah Falgun Tekwani Babu L Avery Mitchell A |
| Affiliation: | aDepartment of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677, USA bNational Center for Natural Products Research, University of Mississippi, University, MS 38677, USA cDepartment of Pharmacology, University of Mississippi, University, MS 38677, USA dDepartment of Chemistry & Biochemistry, University of Mississippi, University, MS 38677, USA |
| 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. |
| Keywords: | Plasmodium falciparum Histone deacetylase Homology modeling Docking Molecular dynamics |
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