The “Gatekeeper” Residue Influences the Mode of Binding of Acetyl Indoles to Bromodomains

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 h...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-04, Vol.59 (7), p.3087-3097
Main Authors: Unzue, Andrea, Zhao, Hongtao, Lolli, Graziano, Dong, Jing, Zhu, Jian, Zechner, Melanie, Dolbois, Aymeric, Caflisch, Amedeo, Nevado, Cristina
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - chemistry
Adaptor Proteins, Signal Transducing - metabolism
Binding Sites
Chemistry Techniques, Synthetic
Computer Simulation
CREB-Binding Protein - chemistry
CREB-Binding Protein - metabolism
Crystallography, X-Ray
Humans
Indoles - chemistry
Indoles - metabolism
Indolizines - chemistry
Indolizines - metabolism
Ligands
Lysine - metabolism
Molecular Docking Simulation
Nuclear Proteins - chemistry
Nuclear Proteins - metabolism
Protein Structure, Tertiary
Proteins - chemistry
Proteins - metabolism
Small Molecule Libraries - chemistry
Small Molecule Libraries - metabolism
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b01757