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Molecules. 2018 Mar 2;23(3). pii: E566. doi: 10.3390/molecules23030566.

A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing.

Author information

1
Department of Pharmaceutical Chemistry, University Halle-Wittenberg, 06120 Halle/Saale, Germany. veranso.conrad@gmail.com.
2
Department of Pharmaceutical Chemistry, University Halle-Wittenberg, 06120 Halle/Saale, Germany. dina.robaa@pharmazie.uni-halle.de.
3
Institute of Pharmaceutical Sciences, University of Freiburg, 79104 Freiburg, Germany. alokta.chakrabarti@gmail.com.
4
Institute of Pharmaceutical Sciences, University of Freiburg, 79104 Freiburg, Germany. karin.schmidtkunz@pharmazie.uni-freiburg.de.
5
Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS, INSERM, B.P. 10142, 67404 Illkirch CEDEX, France. martin.marek@recetox.muni.cz.
6
Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, CNRS, Inserm, CHU Lille, Universite de Lille, F-59000 Lille, France. julien.lancelot@pasteur-lille.fr.
7
Department of Pharmaceutical Chemistry, University Halle-Wittenberg, 06120 Halle/Saale, Germany. raghavk@bii.a-star.edu.sg.
8
Department of Pharmaceutical Chemistry, University Halle-Wittenberg, 06120 Halle/Saale, Germany. jelena.melesina@pharmazie.uni-halle.de.
9
Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS, INSERM, B.P. 10142, 67404 Illkirch CEDEX, France. shaik@igbmc.fr.
10
Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, CNRS, Inserm, CHU Lille, Universite de Lille, F-59000 Lille, France. Raymond.Pierce@pasteur-lille.fr.
11
Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS, INSERM, B.P. 10142, 67404 Illkirch CEDEX, France. romier@igbmc.fr.
12
Institute of Pharmaceutical Sciences, University of Freiburg, 79104 Freiburg, Germany. manfred.jung@pharmazie.uni-freiburg.de.
13
Department of Pharmaceutical Chemistry, University Halle-Wittenberg, 06120 Halle/Saale, Germany. wolfgang.sippl@pharmazie.uni-halle.de.

Abstract

A promising means in the search of new small molecules for the treatment of schistosomiasis (amongst other parasitic ailments) is by targeting the parasitic epigenome. In the present study, a docking based virtual screening procedure using the crystal structure of histone deacetylase 8 from Schistosoma mansoni (smHDAC8) was designed. From the developed screening protocol, we were able to identify eight novel N-(2,5-dioxopyrrolidin-3-yl)-n-alkylhydroxamate derivatives as smHDAC8 inhibitors with IC50 values ranging from 4.4-20.3 µM against smHDAC8. These newly identified inhibitors were further tested against human histone deacetylases (hsHDAC1, 6 and 8), and were found also to be exerting interesting activity against them. In silico prediction of the docking pose of the compounds was confirmed by the resolved crystal structure of one of the identified hits. This confirmed these compounds were able to chelate the catalytic zinc ion in a bidentate fashion, whilst showing an inverted binding mode of the hydroxamate group when compared to the reported smHDAC8/hydroxamates crystal structures. Therefore, they can be considered as new potential scaffold for the development of new smHDAC8 inhibitors by further investigation of their structure-activity relationship.

KEYWORDS:

crystal structure; docking; epigenetics; histone deacetylase (HDAC) inhibitors; schistosomiasis; virtual screening

PMID:
29498707
PMCID:
PMC6017931
DOI:
10.3390/molecules23030566
[Indexed for MEDLINE]
Free PMC Article

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