Publication details

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


SIMOBEN Conrad V. ROBAA Dina CHAKRABARTI Alokta SCHMIDTKUNZ Karin MAREK Martin LANCELOT Julien KANNAN Srinivasaraghavan MELESINA Jelena SHAIK Tajith B. PIERCE Raymond J. ROMIER Christophe JUNG Manfred SIPPL Wolfgang

Year of publication 2018
Type Article in Periodical
Magazine / Source Molecules
MU Faculty or unit

Faculty of Science

Keywords epigenetics; crystal structure; docking; histone deacetylase (HDAC) inhibitors; schistosomiasis; virtual screening
Description 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 mu M 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.

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