The "gatekeeper" residue influences the mode of binding of acetyl indoles to bromodomains

TitleThe "gatekeeper" residue influences the mode of binding of acetyl indoles to bromodomains
Publication TypeJournal Article
Year of Publication2016
AuthorsUnzue A., Zhao H., Lolli G., Dong J., Zhu J., Zechner M., Dolbois A., Caflisch A., Nevado C.
JournalJournal of Medicinal Chemistry
Start Page3087
Date Published2016 Apr 14
Type of ArticleResearch Article
KeywordsAdaptor 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.



Alternate JournalJ. Med. Chem.
PubMed ID26982797
Highlight Role: 
Drug Design