title: Homology modeling of parasite histone deacetylases to guide the structure-based design of selective inhibitors.
abstract: 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.
authors.affiliation: Institute of Pharmacy, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Melesina
authors.affiliation: Institute of Pharmacy, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Dina
authors.initials: D
authors.lastname: Robaa
authors.affiliation: Univ Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Pierce
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM, 1 rue Laurent Fries, B.P. 10142, 67404 Illkirch Cedex, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Romier
authors.affiliation: Institute of Pharmacy, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany. Electronic address: wolfgang.sippl@pharmazie.uni-halle.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry*; D020134:Catalytic Domain; D015801:Helminth Proteins / Q000737:chemistry*; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006655:Histone Deacetylases / Q000737:chemistry*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010963:Plasmodium falciparum / Q000201:enzymology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D015800:Protozoan Proteins / Q000737:chemistry*; D012550:Schistosoma mansoni / Q000201:enzymology; D015032:Zinc / Q000737:chemistry
chemical_list: D000977:Antiparasitic Agents; D015801:Helminth Proteins; D056572:Histone Deacetylase Inhibitors; D015800:Protozoan Proteins; D006655:Histone Deacetylases; D015032:Zinc
keywords: Epigenetics; Histone deacetylases; Homology modeling; Molecular docking; Molecular modeling; Parasitic diseases