The binding of hydroxamic acid derivatives to the active site of HDACs has been studied mainly for the cases of TSA and SAHA, using a bacterial enzyme. The hydroxamic group coordinates the zinc cation in the active site, using both the hydroxamate and carbonyl oxygens. The hydroxamic acid also establishes hydrogen bonds with both histidines belonging to the charge-relay systems, and also with the Tyr-303 hydroxyl group (Fig. 10.20, where the amino acid residues shown correspond to the human HDAC1 enzyme). The hydroxamic acid hydroxyl group replaces the zinc-bound water molecule of the active structure. Additional van der Waals contacts (not shown) are established between hydrophobic amino acid residues and the lipophilic chain in the inhibitor.74

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