Homology Modeling, Docking and Comparative Study of the Selectivity of Some Hdac Inhibitors on Pfhdac-1 and hHdac 8 Models

Abstract

Malaria, one of the problems in many developing countries is caused by the  protozoan parasite called Plasmodium and several cases of the disease are reported annually.

The emergence of multi-drug resistant malarial parasites necessitates the exploration of novel and promising antimalarial enzyme drug target called Plasmodium falciparum histone deacetylase 1 (PfHDAC-1). Thus, in this study, 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 validated using protein structure validation tools. A predictive docking study was carried out using nine sets of known HDAC inhibitors, which have been shown experimentally to have in vitro antimalarial activity against a strain of P. falciparum. Pose validation and score-based active and inactive separation studies provided independent validation of the geometric accuracy and the predictive ability of the generated model. Stereo chemical evaluation using Ramachandran plot revealed that 96.5% residues of the constructed model lie in the most favored and allowed regions, thus, suggesting a good quality model. Comparative analysis was carried out with the human HDAC 8 to ascertain the degree of selectivity of the inhibitors for both models. This revealed that YC-II-88 inhibitor was most selective for PfHDAC-1 model and showed no inhibitory activity for the human HDAC8 model.

Keywords Homology modeling; Plasmodium falciparum; Histone deacetylase; Docking;

Inhibitor