Journal
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
Volume 62, Issue -, Pages 342-361Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jmgm.2015.10.006
Keywords
Histone deacetylases; Molecular modeling; Homology modeling; Molecular docking; Parasitic diseases; Epigenetics
Categories
Funding
- European Union's Seventh Framework Programme [602080]
- Centre National de la Recherche Scientifique (CNRS)
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Universite de Strasbourg
- Universite de Lille
- Institut Pasteur de Lille
- French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05-01]
- Instruct, European Strategy Forum on Research Infrastructures (ESFRI)
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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. (C) 2015 Elsevier Inc. All rights reserved.
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