Fig. 1

Fig. 1

a Top left: Overlay of crystal structures of several HDACs showing the secondary structure elements adjacent to the active site (box on left) and their RMSD to HDAC2 (H1 = HDAC1, H3 = HDAC3, H4 = HDAC4, H6 = HDAC6, H7 = HDAC7, H8 = HDAC8). RMSD is calculated over the conserved secondary structure elements shown in the figure. Number of atoms in the aligned region is mentioned in the table. HDAC2 (green, PDB ID: 5IWG), HDAC4 (cyan, PDB ID: 2VQO), HDAC6 (magenta, PDB ID: 6R0K), HDAC7 (yellow, PDB ID: 3C0Z), HDAC8 (orange, PDB ID: 3SFF). All structures shown here are human variants except HDAC6 (shown by an asterisk), which is the homolog from Danio rerio. The inset on top right shows the overlay of the active site residues of HDAC2 (green) and HDAC6 (magenta). The residues coordinating the active site Zn (gray sphere) are shown in sticks. b Schematic representation of anchor-extension approach. The SHA (2S-2-amino-7-sulfanylheptanoic acid) anchor was inspired by the long tail of the HDAC-binding small molecule Largazole and modeled in HDAC2 pocket. A double bond in Largazole (green box) was replaced by a single bond in SHA to allow synthesis. Low-energy bound conformations were sampled using molecular dynamics simulations and served as starting points for designing new macrocycle binders.