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Cited by 44Histone Deacetylase Inhibitors ResearchComputational Drug Discovery MethodsParasites and Host Interactions

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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Simoben, Conrad, Robaa, Dina, Chakrabarti, Alokta, Schmidtkunz, Karin, Marek, Martin, Lancelot, Julien, Kannan, Srinivasaraghavan, Melesina, Jelena +5 more·2018·Molecules
DOI 10.3390/molecules23030566PMC PMC6017931
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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.

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  • smHDAC8 crystals can be used to look at inhibitor binding in a crystal lattice-unbiased manner.

    “We have previously shown that our smHDAC8 crystals can be used to look at inhibitor binding in a crystal latticeunbiased manner 29, 30, 55-58 .”

    From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [57]

    Section 2.2 (page unavailable) reports an smHDAC8–J1036 crystal structure and describes the inhibitor’s binding in the active-site pocket. Section 3.4 (page unavailable) describes soaking smHDAC8 crystals with J1036. Neither section establishes that the observed binding is unbiased by crystal-lattice contacts. (LLM, conf=0.84)

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Cited by

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Authors
Simoben, C., Robaa, D., Chakrabarti, A., Schmidtkunz, K., Marek, M., Lancelot, J., Kannan, S., Melesina, J., Shaik, T., Pierce, R., Romier, C., Jung, M., & Sippl, W.
Affiliations
  • Martin Luther University Halle-Wittenberg (DE)
  • University of Freiburg (DE)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Sippl, Wolfgang
ORCID
Venue
Molecules
Publisher
MDPI AG
Published
2018-03-02
Volume
23
Issue
3
Pages
566
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules23030566
PMC
PMC6017931
OpenAlex
W2791203388
Cited by
44
References
6
Citations by year
2025: 6 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 7 · 2019: 5 · 2018: 1
FWCI
2.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
  • LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
  • Digitalen Hochschulbibliothek Sachsen-Anhalt (Universitäts- und Landesbibliothek Sachsen-Anhalt) (cc-by)
Funders
  • EU FP7 (241865, 602080)
  • Deutsche Forschungsgemeinschaft (Ju-295/13-1, Si-868/13-1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Immunology and Microbiology › Parasitology › Parasites and Host Interactions
Keywords
Schistosoma mansoni, HDAC8, HDAC8 inhibitors, schistosomiasis, epigenetic drug targets, hydroxamate derivatives, zinc chelation, structure-based virtual screening, structure-activity relationship
MeSH terms
Animals, Anthelmintics, Binding Sites, Chelating Agents, Histone Deacetylases, Hydroxamic Acids, Protein Binding, Pyrrolidines, Schistosoma mansoni, Structure-Activity Relationship, Zinc, Helminth Proteins, Gene Expression, Apoptosis, Protein Structure, Secondary, Crystallography, X-Ray, Protein Interaction Domains and Motifs, Histone Deacetylase Inhibitors, Molecular Docking Simulation

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