5FUE

Crystal structure of Schistosoma mansoni HDAC8 complexed with 3- benzamido-benzohydroxamate

5FUE の概要

• エントリーDOI: 10.2210/pdb5fue/pdb
• 分子名称: HISTONE DEACETYLASE 8, ZINC ION, POTASSIUM ION, ... (7 entities in total)
• 機能のキーワード: hydrolase, platyhelminths, inhibition, histone, deacetylation
• 由来する生物種: SCHISTOSOMA MANSONI
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 204565.20

構造登録者

Marek, M.,Romier, C. (登録日: 2016-01-26, 公開日: 2016-03-09, 最終更新日: 2024-05-08)

主引用文献

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

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: 26937828
DOI: 10.1021/ACS.JMEDCHEM.5B01478

実験手法

X-RAY DIFFRACTION (2.199 Å)