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.

The "gatekeeper" Residue Influences the Mode of Binding of Acetyl Indoles to Bromodomains / Unzue, Andrea; Zhao, Hongtao; Lolli, Graziano; Dong, Jing; Zhu, Jian; Zechner, Melanie; Dolbois, Aymeric; Caflisch, Amedeo; Nevado, Cristina. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 59:7(2016), pp. 3087-3097. [10.1021/acs.jmedchem.5b01757]

The "gatekeeper" Residue Influences the Mode of Binding of Acetyl Indoles to Bromodomains

Lolli, Graziano;
2016

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.
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Unzue, Andrea; Zhao, Hongtao; Lolli, Graziano; Dong, Jing; Zhu, Jian; Zechner, Melanie; Dolbois, Aymeric; Caflisch, Amedeo; Nevado, Cristina
The "gatekeeper" Residue Influences the Mode of Binding of Acetyl Indoles to Bromodomains / Unzue, Andrea; Zhao, Hongtao; Lolli, Graziano; Dong, Jing; Zhu, Jian; Zechner, Melanie; Dolbois, Aymeric; Caflisch, Amedeo; Nevado, Cristina. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 59:7(2016), pp. 3087-3097. [10.1021/acs.jmedchem.5b01757]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11572/154366
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