5FUE
Crystal structure of Schistosoma mansoni HDAC8 complexed with 3- benzamido-benzohydroxamate
Summary for 5FUE
Entry DOI | 10.2210/pdb5fue/pdb |
Descriptor | HISTONE DEACETYLASE 8, ZINC ION, POTASSIUM ION, ... (7 entities in total) |
Functional Keywords | hydrolase, platyhelminths, inhibition, histone, deacetylation |
Biological source | SCHISTOSOMA MANSONI |
Total number of polymer chains | 4 |
Total formula weight | 204565.20 |
Authors | Marek, M.,Romier, C. (deposition date: 2016-01-26, release date: 2016-03-09, Last modification date: 2024-05-08) |
Primary citation | Heimburg, T.,Chakrabarti, A.,Lancelot, J.,Marek, M.,Melesina, J.,Hauser, A.T.,Shaik, T.B.,Duclaud, S.,Robaa, D.,Erdmann, F.,Schmidt, M.,Romier, C.,Pierce, R.J.,Jung, M.,Sippl, W. Structure-Based Design and Synthesis of Novel Inhibitors Targeting Hdac8 from Schistosoma Mansoni for the Treatment of Schistosomiasis. J.Med.Chem., 59:2423-, 2016 Cited by PubMed Abstract: Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, a series of new benzohydroxamates were prepared as potent inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by these 3-amidobenzohydroxamates. The newly designed inhibitors were evaluated in screens for enzyme inhibitory activity against schistosome and human HDACs. Twenty-seven compounds were found to be active in the nanomolar range, and some of them showed selectivity toward smHDAC8 over the major human HDACs (1 and 6). The active benzohydroxamates were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Four of these showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture. PubMed: 26937828DOI: 10.1021/ACS.JMEDCHEM.5B01478 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.199 Å) |
Structure validation
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