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Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.

Original publication

DOI

10.1021/jm4011302

Type

Journal article

Journal

J Med Chem

Publication Date

24/10/2013

Volume

56

Pages

8073 - 8088

Keywords

Computational Biology, Crystallography, X-Ray, Drug Discovery, Humans, Models, Molecular, Molecular Structure, Nuclear Proteins, Protein Binding, Protein Structure, Tertiary, Reproducibility of Results, Small Molecule Libraries, Structure-Activity Relationship, Transcription Factors