epresentative structures of the main classes of known histone deacteylase (HDAC) inhibitors (HDACi), either from natural sources (a) or synthetic (b). In HDACs, the active site of the enzyme (containing the zinc atom) occupies the bottom of a channel delimited by a rim, which corresponds to the substrate pocket (acetyl-lysine). The schematic view of the HDACi 'pharmacophore' (c) therefore consists of: a metal-binding domain (ZnC), which chelates zinc and blocks the enzymatic activity; a linker domain, which mimics the substrate and occupies the enzymatic channel (PCU and HS: polar connecting unit and hydrophobic spacer, respectively); and a surface domain, which makes contacts with the rim71. The structures of the HDACi chemical groups that carry out these processes are shown below each of the yellow boxes, as indicated by the arrows.