6tld

Crystal structure of Schistosoma mansoni HDAC8 complexed with a triazole hydroxamate inhibitor 2

spinqualitylabelsall models 6tld, resolution 1.61Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6tld is a 4 chain structure with sequence from Schistosoma mansoni. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.61Å Ligands: DMF, GOL, K, NK5, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A5H660_SCHMA Publication Abstract from PubMed Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma , which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial screening revealed the triazole-based hydroxamate 2b exhibiting potent inhibitory activity toward the novel antiparasitic target Schistosoma mansoni histone deacetylase 8 (smHDAC8) and promising selectivity over the major human HDACs. Subsequent crystallographic studies of the 2b /smHDAC8 complex revealed key interactions between the inhibitor and the enzyme's active site, thus explaining the unique selectivity profile of the inhibitor. Further chemical modifications of 2b led to the discovery of 4-fluorophenoxy derivative 21 , a nanomolar smHDAC8 inhibitor (IC 50 = 0.5 microM), exceeding the smHDAC8 inhibitory activity of 2b and SAHA, while exhibiting an improved selectivity profile over the investigated human HDACs. Collectively, this study reveals specific interactions between smHDAC8 and the synthesized triazole-based inhibitors and demonstrates that these small molecules represent promising lead structures, which could be further developed in the search for novel drugs for the treatment of schistosomiasis. Structure-Based Design, Synthesis, and Biological Evaluation of Triazole-Based smHDAC8 Inhibitors.,Holl R, Kalinin DV, Jana SK, Pfafenrot M, Chakrabarti A, Melesina J, Shaik TB, Lancelot J, Pierce RJ, Sippl W, Romier C, Jung M ChemMedChem. 2019 Dec 9. doi: 10.1002/cmdc.201900583. PMID:31816172 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone deacetylase 3D structures

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