A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing
| Autor: | Raymond J. Pierce, Wolfgang Sippl, Julien Lancelot, Karin Schmidtkunz, Alokta Chakrabarti, Dina Robaa, Jelena Melesina, Tajith B. Shaik, Christophe Romier, Conrad V. Simoben, Manfred Jung, Srinivasaraghavan Kannan, Martin Marek |
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| Přispěvatelé: | Romier, Christophe, Martin-Luther-Universität Halle Wittenberg (MLU), Albert-Ludwigs-Universität Freiburg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), This work and the authors of this article received funding from the European Union’s Seventh Framework Programme for Research, Technological Development and Demonstration under Grant Agreements 241865 (SEtTReND) and 602080 (A-ParaDDisE). Further support was received by the Deutsche Forschungsgemeinschaft (Ju-295/13-1, SI-868/13-1). MM, TBS and CR are supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Université de Strasbourg., The authors acknowledge the support and the use of resources of the French Infrastructure for Integrated Structural Biology FRISBI ANR-10-INBS-05 and of Instruct-ERIC. We wish to thank members of the ESRF-EMBL joint structural biology groups and the SOLEIL synchrotron for the use of their beamline facilities and for help during data collection. We are grateful to Pierre Legrand (SOLEIL) for his kind assistance for data processing, Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pyrrolidines MESH: Helminth Proteins/metabolism MESH: Histone Deacetylases/metabolism MESH: Histone Deacetylases/genetics Pharmaceutical Science MESH: Protein Structure Secondary Gene Expression Apoptosis Crystallography X-Ray Hydroxamic Acids Molecular Docking Simulation MESH: Helminth Proteins/antagonists & inhibitors MESH: Chelating Agents/chemical synthesis Protein Structure Secondary Analytical Chemistry 0302 clinical medicine MESH: Structure-Activity Relationship MESH: Hydroxamic Acids/chemical synthesis Drug Discovery MESH: Zinc/metabolism MESH: Animals [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] MESH: Histone Deacetylase Inhibitors/pharmacology Chelating Agents Anthelmintics biology Chemistry MESH: Anthelmintics/pharmacology Helminth Proteins Schistosoma mansoni epigenetics crystal structure docking histone deacetylase (HDAC) inhibitors schistosomiasis virtual screening MESH: Histone Deacetylases/chemistry 3. Good health MESH: Schistosoma mansoni/drug effects MESH: Pyrrolidines/pharmacology Zinc Biochemistry Chemistry (miscellaneous) Molecular Medicine Protein Binding MESH: Apoptosis/drug effects MESH: Gene Expression In silico 030231 tropical medicine MESH: Zinc/chemistry Article Histone Deacetylases lcsh:QD241-441 03 medical and health sciences Structure-Activity Relationship lcsh:Organic chemistry MESH: Molecular Docking Simulation Structure–activity relationship MESH: Protein Binding Animals MESH: Helminth Proteins/genetics Protein Interaction Domains and Motifs Physical and Theoretical Chemistry MESH: Histone Deacetylase Inhibitors/chemical synthesis [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Virtual screening MESH: Protein Interaction Domains and Motifs Binding Sites Organic Chemistry MESH: Hydroxamic Acids/pharmacology HDAC8 MESH: Schistosoma mansoni/growth & development Epigenome biology.organism_classification MESH: Crystallography X-Ray MESH: Anthelmintics/chemical synthesis Histone Deacetylase Inhibitors 030104 developmental biology MESH: Binding Sites Docking (molecular) MESH: Chelating Agents/pharmacology MESH: Schistosoma mansoni/enzymology MESH: Helminth Proteins/chemistry MESH: Schistosoma mansoni/genetics MESH: Pyrrolidines/chemical synthesis |
| Zdroj: | Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry Molecules Molecules, 2018, 23 (3), pp.566. ⟨10.3390/molecules23030566⟩ Molecules, Vol 23, Iss 3, p 566 (2018) Molecules; Volume 23; Issue 3; Pages: 566 Molecules, MDPI, 2018, 23 (3), pp.566. ⟨10.3390/molecules23030566⟩ |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules23030566⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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