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

Conrad Simoben (1) , Dina Robaa (1) , Alokta Chakrabarti (2) , Karin Schmidtkunz (2) , Martin Marek (3) , Julien Lancelot (4) , Srinivasaraghavan Kannan (1) , Jelena Melesina (1) , Tajith Shaik (3) , Raymond J. Pierce (4) , Christophe Romier (3) , Manfred Jung (2) , Wolfgang Sippl (1)

1 MLU - Martin-Luther-Universität Halle Wittenberg
2 Albert-Ludwigs-Universität Freiburg
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
4 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204

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.

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

Domaines: Biochimie [q-bio.BM]

Conrad Simoben, Dina Robaa, Alokta Chakrabarti, Karin Schmidtkunz, Martin Marek, et al.. A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing. Molecules, 2018, 23 (3), pp.566. ⟨10.3390/molecules23030566⟩. ⟨hal-02391176⟩