Homology modeling of parasite histone deacetylases to guide the structure-based design of selective inhibitors.
Histone deacetylases (HDACs) are promising epigenetic targets for the treatment of various diseases, including cancer and neurodegenerative disorders. There is evidence that they can also be addressed to treat parasitic infections. Recently, the first X-ray structure of a parasite HDAC was published, Schistosoma mansoni HDAC8, giving structural insights into its inhibition. However, most of the targets from parasites of interest still lack this structural information. Therefore, we prepared homology models of relevant parasitic HDACs and compared them to human and S. mansoni HDACs. The information about known S. mansoni HDAC8 inhibitors and compounds that affect the growth of Trypanosoma, Leishmania and Plasmodium species was used to validate the models by docking and molecular dynamics studies. Our results provide analysis of structural features of parasitic HDACs and should be helpful for selecting promising candidates for biological testing and for structure-based optimisation of parasite-specific inhibitors.
['Melesina|Jelena|J|', 'Robaa|Dina|D|', 'Pierce|Raymond J|RJ|', 'Romier|Christophe|C|', 'Sippl|Wolfgang|W|']
D000818:Animals D000977:Antiparasitic Agents D020134:Catalytic Domain D015801:Helminth Proteins D056572:Histone Deacetylase Inhibitors D006655:Histone Deacetylases D062105:Molecular Docking Simulation D056004:Molecular Dynamics Simulation D010963:Plasmodium falciparum D011485:Protein Binding D017433:Protein Structure, Secondary D015800:Protozoan Proteins D012550:Schistosoma mansoni D015032:Zinc
Homology modeling Histone deacetylases Epigenetics Molecular docking Molecular modeling Parasitic diseases