Journal of Natural Sciences Research www.iiste.org ISSN 2224-3186 (Paper) ISSN 2225-0921 (Online) Vol.3, No.6, 2013 38 Homology Modeling, Docking and Comparative Study of the Selectivity of Some Hdac Inhibitors on Pfhdac-1 and hHdac 8 Models Nnenna Winifred Odozi 1* Moriam Dasola Adeoye 2 1. Department of Chemistry, University of Ibadan, Ibadan, Nigeria. 2. Department of Chemical Sciences, Fountain University, Osogbo, Nigeria. *E-mail of the corresponding author: nw.odozi@ui.edu.ng 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 1. Introduction Malaria being a mosquito-borne infectious disease caused by protozoan parasites (Plasmodium) is widely spread in tropical and subtropical regions of the world. Approximately 500 million clinical cases of malaria are reported each year, of which 1-2 million result in death. 90% of the deaths occur in sub-Saharan Africa and most are children under the age of five. 50 million of the reported cases are pregnant women. Malaria in pregnancy contributes to nearly 20% low birth weight babies and also causes stillbirth and maternal deaths 1-3 . There are four known species of the Plasmodium that infect humans. These include P. falciparum, P. vivax, P. malariae and P. oval. Unfortunately, P. falciparum causes most of the severity and deaths attributed to the disease. They have become increasingly resistant to the currently used drugs; even the Artemisinin based Combination Therapies (ACTs) 4 . Due to this fact, development of drugs attacking crucial targets in the metabolism or mechanism of action of the malaria pathogen is imperative. The histone deacetylases (HDACs) of P. falciparum are tipped as potential targets for new classes of antimalarial drugs. Histones are highly alkaline proteins found in eukaryotic cell nuclei and play a role in gene regulation. A number of HDAC are present in humans and can be classified into four categories 5 class I (HDAC 1,2,3,8), class II (HDAC 4,5,6,7,9,10), class III (Sirtuins), class IV (HDAC 11). The HDACS from classes I, II and IV exhibit zinc dependent mechanisms while the Sirtuins which are NAD + dependent demonstrates ADP-ribosyltransferase activity in addition to deacetylase activity 6 . HDAC inhibitors interfere with the functions of HDAC by arresting cell growth, inducing differentiation as well as apoptotic cell death. Generally, inhibitors show little selectivity for plasmodium cells compared with their selectivity for human cells 8 . For an outstanding success in the discovery of new and potent drugs, emphasis must be laid on the use of inhibitors that are selective towards the plasmodium cells even at very low concentrations. This paper therefore presents the homology model of PfHDAC1 and compares the results obtained from docking of selected inhibitors on PfHDAC 1 and human HDAC 8 models to that obtained experimentally (using the same inhibitors) as reported by Agbor-Enoh et al 8 . 2. Department of Chemical Sciences, Fountain University, Osogbo, Nigeria. 3. Department of Chemistry, Denmark Technical University, Denmark Peter Fristrup 3