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

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 (smHDAC8...

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Published in:	Molecules (Basel, Switzerland) Switzerland), 2018-03, Vol.23 (3), p.566
Main Authors:	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
Format:	Article
Language:	eng
Subjects:	Animals Anthelmintics - chemical synthesis Anthelmintics - pharmacology Apoptosis - drug effects Binding Sites Biochemistry Biochemistry, Molecular Biology Catalysis Chelates Chelating Agents - chemical synthesis Chelating Agents - pharmacology Chromatin Crystal structure Crystallography, X-Ray Docking epigenetics Gene Expression Helminth Proteins - antagonists & inhibitors Helminth Proteins - chemistry Helminth Proteins - genetics Helminth Proteins - metabolism Histone deacetylase histone deacetylase (HDAC) inhibitors Histone Deacetylase Inhibitors - chemical synthesis Histone Deacetylase Inhibitors - pharmacology Histone Deacetylases - chemistry Histone Deacetylases - genetics Histone Deacetylases - metabolism Hydroxamic Acids - chemical synthesis Hydroxamic Acids - pharmacology In vitro methods and tests Inhibitors Life Sciences Molecular Docking Simulation Protein Binding Protein Interaction Domains and Motifs Protein Structure, Secondary Pyrrolidines - chemical synthesis Pyrrolidines - pharmacology Schistosoma mansoni Schistosoma mansoni - drug effects Schistosoma mansoni - enzymology Schistosoma mansoni - genetics Schistosoma mansoni - growth & development Schistosomiasis Screening Structure-Activity Relationship virtual screening Zinc Zinc - chemistry Zinc - metabolism
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Summary:	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 (smHDAC8) was designed. From the developed screening protocol, we were able to identify eight novel -(2,5-dioxopyrrolidin-3-yl)- -alkylhydroxamate derivatives as smHDAC8 inhibitors with IC 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.
ISSN:	1420-3049 1420-3049