Titre :

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

Auteur(s) :

Simoben, Conrad [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Robaa, Dina [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Chakrabarti, Alokta [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Schmidtkunz, Karin [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Marek, Martin [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Lancelot, Julien [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Kannan, Srinivasaraghavan [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Melesina, Jelena [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Shaik, Tajith [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Pierce, Raymond [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Romier, Christophe [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Jung, Manfred [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Sippl, Wolfgang [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]

Titre de la revue :

Molecules

Pagination :

566

Éditeur :

MDPI

Date de publication :

2018-03

ISSN :

1420-3049

Mot(s)-clé(s) en anglais :

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

Discipline(s) HAL :

Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire/Biochimie [q-bio.BM]

Résumé en anglais : [en]

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 ...
Lire la suite >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.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Projet ANR :

Infrastructure Française pour la Biologie Structurale Intégrée

Collections :

• Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017

Source :

Harvested from HAL