The "gatekeeper" residue influences the mode of binding of acetyl indoles to bromodomains
| Title | The "gatekeeper" residue influences the mode of binding of acetyl indoles to bromodomains |
| Publication Type | Journal Article |
| Year of Publication | 2016 |
| Authors | Unzue A., Zhao H., Lolli G., Dong J., Zhu J., Zechner M., Dolbois A., Caflisch A., Nevado C. |
| Journal | Journal of Medicinal Chemistry |
| Volume | 59 |
| Start Page | 3087 |
| Issue | 7 |
| Pagination | 3087-3097 |
| Date Published | 2016 Apr 14 |
| Type of Article | Research Article |
| Keywords | 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 |
| 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. |
| DOI | 10.1021/acs.jmedchem.5b01757 |
| pubindex | 0213 |
| Alternate Journal | J. Med. Chem. |
| PubMed ID | 26982797 |
Full Text PDF:
SI PDF:
Highlight Role:
Drug Design