6fu1
Crystal structure of Schistosoma mansoni HDAC8 complexed with a n-alkyl hydroxamateCrystal structure of Schistosoma mansoni HDAC8 complexed with a n-alkyl hydroxamate
Structural highlights
FunctionPublication Abstract from PubMedA 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 microM 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. A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing.,Simoben CV, Robaa D, Chakrabarti A, Schmidtkunz K, Marek M, Lancelot J, Kannan S, Melesina J, Shaik TB, Pierce RJ, Romier C, Jung M, Sippl W Molecules. 2018 Mar 2;23(3). pii: molecules23030566. doi:, 10.3390/molecules23030566. PMID:29498707[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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