Homology modeling, docking, and a comparative study of the selectivity of a few Hdac inhibitors on PfHdac-1 and hHdac models Nnenna Winifred Odozi 1 , Peter Fristrup 2 1 Department of Chemistry, University of Ibadan, Nigeria, 2 Department of Chemistry, Denmark Technical University, Denmark The protozoan parasite Plasmodium is what causes malaria, which is one of the issues in many underdeveloped nations. Each year, several cases of the disease are documented. Exploring Plasmodium falciparum histone deacetylase 1 (PfHDAC-1) as a novel and prospective antimalarial enzyme therapeutic target is necessary in light of the advent of multi-drug resistant malarial parasites. Thus, in this investigation, a restraint-guided optimization approach utilizing the OPLS/GBSA potential setup was used to construct a ligand-refined homology model of PfHDAC-1 from the crystal structures of human HDAC8 and HDLP. Tools for protein structural validation were used to verify the model. Nine sets of well-known HDAC inhibitors that have been empirically demonstrated to have in vitro antimalarial activity against a strain of P. falciparum were used in a predictive docking investigation. The geometrical accuracy and predictive capability of the model generated were independently validated by pose validation and score based active and inactive separate studies. The stereo chemical evaluation using Ramachandran plots showed 96.5 % of the model residue lying in the most preferred and permissible regions, indicating a high quality model. A comparative analysis was conducted with the human HDAC 8 to determine the selectivity of inhibitors for the two models. The YC- II-88 inhibitor showed the most selectivity for the PfHDAC -1 model and did not show any inhibitory activity in the human HDAC-8 model. References
1. WHO. World Malaria Report 2008; Geneva: World Health Organization, 2008. 2. WHO. World Malaria Report 2022; Geneva: World Health Organization, 2022. 3. Malaria and Children, Report on Progress in Intervention Coverage, 2010. UNICEF
P59
© The Author(s), 2023
Made with FlippingBook Learn more on our blog