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. 2021 Aug 25;26(17):5151. doi: 10.3390/molecules26175151

Figure 6.

Figure 6

(A) Overlay of HDAC2 (PDB ID: 4LY1/ochre, 3MAX/magenta, and 5IX0/green). Three ligands with aryl substitutions indicated below protrude into the foot pocket and displace the F110 residue with increasing steric demand as indicated by the arrow. (B) Overlay of HDAC1–3 (PDB ID: HDAC1, 4BKX/magenta; HDAC2, 7LTK/ochre; HDAC3, 4A69/green) and visualization of the surface area around the foot pocket. The surfaces of the foot pocket of HDAC1 (magenta), HDAC2 (ochre), and HDAC3 (green) are shown as mesh. Residues are numbered according to HDAC2 (PDB ID: 7LTK). M31, Y304, and C152 undergo displacement as indicated by the arrows, successively widening the foot pocket from HDAC1 to HDAC3. Rotamers for L140 are indicated with curly arrows and illustrate a gatekeeping property. Metal bonds to zinc-binding residues D265, H179, and D177 are illustrated as orange dotted lines. (C) 2D ligand interactions of (A) overlaid HDAC2 crystal structures with PDB IDs 4LY1, 3MAX, and 5IXO. (D) Schematic SAR of amino benzamide warheads with indicated spheres as placeholders for substituents within the clipped binding pocket of HDAC2 (PDB ID: 4LY1). Metal bonds are indicated as orange dotted lines.