Figure 15.

(A) Structural overlay of HDAC2 complexed with ketones 55 and 61 (PDB ID: 6XDM/yellow and 6WBW/red) and a hydroxamate (PDB ID: 4LXZ/green). Shown is the clipped binding pocket with the zinc ion as a gray sphere and metal contacts in yellow and blue for the hydroxamate and the diol moiety, respectively. (B) Structural overlay of HDAC4 complexed with a hydroxamate prepared by Bürli et al. [125] in a closed conformation (4CBY/green) and 62 by Bottomley et al. [124] in an open conformation (2VQJ/red), indicating large induced conformational changes of the foot pocket, which might be exploitable for further drug and warhead design. (C) Ligand interactions of the hydroxamic acid by Bürli et al. [125] and 62 within the canonical binding site of HDAC4. (D) Binding mode of ketones with a short SAR summary for the warhead.