A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing
| العنوان: | A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing |
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| المؤلفون: | 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 |
| المساهمون: | 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) |
| المصدر: | 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⟩ |
| بيانات النشر: | MDPI, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1420-3049 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c57756972e5c4439f4e393638be3994bTest http://europepmc.org/articles/PMC6017931Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c57756972e5c4439f4e393638be3994b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14203049 |
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