Next Article in Journal
Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search
Previous Article in Journal
New Drug Candidate Targeting the 4A1 Orphan Nuclear Receptor for Medullary Thyroid Cancer Therapy
Previous Article in Special Issue
The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors
Article Menu
Issue 3 (March) cover image

Export Article

Open AccessFeature PaperArticle
Molecules 2018, 23(3), 566; https://doi.org/10.3390/molecules23030566

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

1
Department of Pharmaceutical Chemistry, University Halle-Wittenberg, 06120 Halle/Saale, Germany
2
Institute of Pharmaceutical Sciences, University of Freiburg, 79104 Freiburg, Germany
3
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
4
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
Current address: ProQinase GmbH, 79106 Freiburg, Germany
Current address: Loschmidt Laboratories, Department of Experimental Biology & Recetox, Masaryk University, 625 00 Brno, Czech Republic
§
Current address: Bioinformatics Institute (A*STAR), #07-01 Matrix, 138671 Singapore, Singapore
*
Author to whom correspondence should be addressed.
Received: 30 January 2018 / Revised: 23 February 2018 / Accepted: 28 February 2018 / Published: 2 March 2018
(This article belongs to the Special Issue Modulators of Histone Acetylation: A Medicinal Chemistry Perspective)
Full-Text   |   PDF [4448 KB, uploaded 2 March 2018]   |  

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. View Full-Text
Keywords: epigenetics; crystal structure; docking; histone deacetylase (HDAC) inhibitors; schistosomiasis; virtual screening epigenetics; crystal structure; docking; histone deacetylase (HDAC) inhibitors; schistosomiasis; virtual screening
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Simoben, C.V.; Robaa, D.; Chakrabarti, A.; Schmidtkunz, K.; Marek, M.; Lancelot, J.; Kannan, S.; Melesina, J.; Shaik, T.B.; Pierce, R.J.; Romier, C.; Jung, M.; Sippl, W. A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing. Molecules 2018, 23, 566.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top