We analyze 20 crystal structures of complexes between the CBP bromodomain and small-molecule ligands that belong to eight different chemotypes identified by docking. The binding motif of the moiety that mimics the natural ligand (acetylated side chain of lysine) at the bottom of the binding pocket is conserved. In stark contrast, the rest of the ligands form different interactions with different side chains and backbone polar groups on the outer rim of the binding pocket. Hydrogen bonds are direct or water-bridged. van der Waals contacts are optimized by rotations of hydrophobic side chains and a slight inward displacement of the ZA loop. Rare types of interactions are observed for some of the ligands.
BT - ACS Med Chem Lett C1 - 0240 DA - 2018 Sep 13 DO - 10.1021/acsmedchemlett.8b00286 IS - 9 J2 - ACS Med. Chem. Lett. LA - eng M3 - Research Article N2 -We analyze 20 crystal structures of complexes between the CBP bromodomain and small-molecule ligands that belong to eight different chemotypes identified by docking. The binding motif of the moiety that mimics the natural ligand (acetylated side chain of lysine) at the bottom of the binding pocket is conserved. In stark contrast, the rest of the ligands form different interactions with different side chains and backbone polar groups on the outer rim of the binding pocket. Hydrogen bonds are direct or water-bridged. van der Waals contacts are optimized by rotations of hydrophobic side chains and a slight inward displacement of the ZA loop. Rare types of interactions are observed for some of the ligands.
PY - 2018 SP - 929 EP - 934 T2 - ACS Med Chem Lett TI - Binding motifs in the CBP Bromodomain: an analysis of 20 crystal structures of complexes with small molecules VL - 9 SN - 1948-5875 ER -