On the inhibition of histone deacetylase 8.
Histone deacetylases are key regulators of gene expression and have recently emerged as important therapeutic targets for cancer and a growing number of non-malignant diseases. Many widely studied inhibitors of HDACs such as SAHA are thought to have low selectivity within or between the human HDAC isoform classes. Using an isoform-selective assay, we have shown that a number of the known inhibitors have in fact a low activity against HDAC8. Based on the wealth of structural information available for human HDAC8, we use a combination of docking and molecular dynamics simulations to determine the structural origin of the experimental results. A close relationship is found between the activity and the high surface malleability of HDAC8. These results provide a rationale for the recently described 'linkerless' HDAC8 selective inhibitors and design criteria for HDAC8 selective inhibitors.
Estiu
Guillermina
G
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556-5670, USA.
West
Nathan
N
Mazitschek
Ralph
R
Greenberg
Edward
E
Bradner
James E
JE
Wiest
Olaf
O
D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006655:Histone Deacetylases; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D020033:Protein Isoforms; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
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