7P3S

Crystal structure of Schistosoma mansoni HDAC8 complexed with a benzohydroxamate inhibitor 12

7P3S の概要

• エントリーDOI: 10.2210/pdb7p3s/pdb
• 分子名称: Histone deacetylase, ZINC ION, POTASSIUM ION, ... (6 entities in total)
• 機能のキーワード: epigenetics, histone deacetylase, hdac8, selective inhibitor, pathogen, hydrolase
• 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: 205148.73

構造登録者

Shaik, T.B.,Romier, C. (登録日: 2021-07-08, 公開日: 2021-09-15, 最終更新日: 2024-01-31)

主引用文献

Ghazy, E.,Heimburg, T.,Lancelot, J.,Zeyen, P.,Schmidtkunz, K.,Truhn, A.,Darwish, S.,Simoben, C.V.,Shaik, T.B.,Erdmann, F.,Schmidt, M.,Robaa, D.,Romier, C.,Jung, M.,Pierce, R.,Sippl, W.
Synthesis, structure-activity relationships, cocrystallization and cellular characterization of novel smHDAC8 inhibitors for the treatment of schistosomiasis.
Eur.J.Med.Chem., 225:113745-113745, 2021

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, we chemically optimized our previously reported benzhydroxamate-based inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by the highly potent inhibitor 5o. Structure-based optimization of the novel inhibitors was carried out using the available crystal structures as well as docking studies on smHDAC8. The compounds were evaluated in screens for inhibitory activity against schistosome and human HDACs (hHDAC). The in vitro and docking results were used for detailed structure activity relationships. The synthesized compounds were further investigated for their lethality against the schistosome larval stage using a fluorescence-based assay. The most promising inhibitor 5o showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.

PubMed: 34392190
DOI: 10.1016/j.ejmech.2021.113745

実験手法

X-RAY DIFFRACTION (1.546 Å)