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

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• 作者：Andrea Unzue ; Hongtao Zhao ; Graziano Lolli ; Jing Dong ; Jian Zhu ; Melanie Zechner ; Aymeric Dolbois ; Amedeo Caflisch ; Cristina Nevado
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3087-3097
• 全文大小：685K
• 年卷期：0
• ISSN：1520-4804

文摘

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.