Download MendeleyThe "Gatekeeper" Residue Influences the Mode of Binding of Acetyl Indoles to Bromodomains.
Unzue, A., Zhao, H., Lolli, G., Dong, J., Zhu, J., Zechner, M., Dolbois, A., Caflisch, A., Nevado, C.(2016) J Med Chem 59: 3087-3097
- PubMed: 26982797
- DOI: https://doi.org/10.1021/acs.jmedchem.5b01757
- Primary Citation of Related Structures:
5D7X, 5E73, 5E74 - PubMed Abstract:
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.
Organizational Affiliation:
Department of Chemistry and ‡Department of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
