期刊
MOLECULES
卷 23, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/molecules23030566
关键词
epigenetics; crystal structure; docking; histone deacetylase (HDAC) inhibitors; schistosomiasis; virtual screening
资金
- European Union [241865, 602080]
- Deutsche Forschungsgemeinschaft [Ju-295/13-1, SI-868/13-1]
- Centre National de la Recherche Scientifique (CNRS)
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Universite de Strasbourg
- French Infrastructure for Integrated Structural Biology FRISBI [ANR-10-INBS-05]
- Instruct-ERIC
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 mu M 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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