Small-molecule hits for the bromodomains of CREBBP and BAZ2B have been identified by scaffold hopping followed by docking of a set of ∼200 compounds containing the acetyl indole scaffold. Chemical synthesis of nearly 30 derivatives has resulted in ligands of representatives of three subfamilies of human bromodomains with favorable ligand efficiency. The X-ray crystal structures of three different bromodomains (CREBBP, BAZ2B, and BRPF1b) in complex with acetyl indole derivatives reveal the influence of the gatekeeper residue on the orientation of small-molecule ligands in the acetyl lysine binding site.
BT - Journal of Medicinal Chemistry C1 - 0213 DA - 2016 Apr 14 DO - 10.1021/acs.jmedchem.5b01757 IS - 7 J2 - J. Med. Chem. LA - eng M3 - Research Article N2 -Small-molecule hits for the bromodomains of CREBBP and BAZ2B have been identified by scaffold hopping followed by docking of a set of ∼200 compounds containing the acetyl indole scaffold. Chemical synthesis of nearly 30 derivatives has resulted in ligands of representatives of three subfamilies of human bromodomains with favorable ligand efficiency. The X-ray crystal structures of three different bromodomains (CREBBP, BAZ2B, and BRPF1b) in complex with acetyl indole derivatives reveal the influence of the gatekeeper residue on the orientation of small-molecule ligands in the acetyl lysine binding site.
PY - 2016 SE - 3087 SP - 3087 EP - 3097 T2 - Journal of Medicinal Chemistry TI - The "gatekeeper" residue influences the mode of binding of acetyl indoles to bromodomains VL - 59 SN - 1520-4804 ER -