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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / metabolism
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Binding Sites
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CREB-Binding Protein / chemistry
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CREB-Binding Protein / metabolism
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Chemistry Techniques, Synthetic
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Computer Simulation
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Crystallography, X-Ray
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DNA-Binding Proteins
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Humans
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Indoles / chemistry*
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Indoles / metabolism
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Indolizines / chemistry
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Indolizines / metabolism
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Ligands
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Lysine / metabolism
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Molecular Docking Simulation
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Nuclear Proteins / chemistry
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Nuclear Proteins / metabolism
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Protein Structure, Tertiary
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Proteins / chemistry
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Proteins / metabolism*
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Small Molecule Libraries / chemistry*
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Small Molecule Libraries / metabolism*
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Transcription Factors, General
Substances
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Adaptor Proteins, Signal Transducing
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BAZ2B protein, human
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BRPF1 protein, human
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DNA-Binding Proteins
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Indoles
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Indolizines
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Ligands
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Nuclear Proteins
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Proteins
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Small Molecule Libraries
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Transcription Factors, General
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indolizine
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CREB-Binding Protein
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CREBBP protein, human
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Lysine