A. Unzue; H. Zhao; G. Lolli; J. Dong; J. Zhu; M. Zechner; A. Dolbois; A. Caflisch; C. Nevado

Journal: J. Med. Chem.
Year: 2016
Volume: 59
Issue: 7
Pages: 3087-3097
DOI: 10.1021/acs.jmedchem.5b01757
Type of Publication: Journal Article

Adaptor Proteins, Signal Transducing; Binding Sites; Chemistry Techniques, Synthetic; Computer Simulation; CREB-Binding Protein; Crystallography, X-Ray; Humans; Indoles; Indolizines; Ligands; Lysine; Molecular Docking Simulation; Nuclear Proteins; Protein Structure, Tertiary; Proteins; Small Molecule Libraries


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.