6FU1
Crystal structure of Schistosoma mansoni HDAC8 complexed with a n-alkyl hydroxamate
Summary for 6FU1
| Entry DOI | 10.2210/pdb6fu1/pdb |
| Descriptor | Histone deacetylase, ZINC ION, POTASSIUM ION, ... (6 entities in total) |
| Functional Keywords | epigenetics, histone deacetylase, hdac8, selective inhibitor, pathogen, hydrolase |
| Biological source | Schistosoma mansoni (Blood fluke) |
| Total number of polymer chains | 4 |
| Total formula weight | 203985.35 |
| Authors | Marek, M.,Shaik, T.B.,Romier, C. (deposition date: 2018-02-26, release date: 2019-03-13, Last modification date: 2024-05-08) |
| Primary citation | Simoben, C.V.,Robaa, D.,Chakrabarti, A.,Schmidtkunz, K.,Marek, M.,Lancelot, J.,Kannan, S.,Melesina, J.,Shaik, T.B.,Pierce, R.J.,Romier, C.,Jung, M.,Sippl, W. A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing. Molecules, 23:-, 2018 Cited by PubMed 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 (smHDAC8) was designed. From the developed screening protocol, we were able to identify eight novel -(2,5-dioxopyrrolidin-3-yl)--alkylhydroxamate derivatives as smHDAC8 inhibitors with IC 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. PubMed: 29498707DOI: 10.3390/molecules23030566 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.548 Å) |
Structure validation
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