부산대학교 도서관

Bromodomains(BRDs) are epigenetic readers that recognize acetylated-lysine(KAc) on proteins and are implicated in a number of diseases. We describea virtual screening approach to identify BRD inhibitors. Key elementsof this approach are the extensive design and use of substructurequeries to compile a set of commercially available compounds featuringnovel putative KAc mimetics and docking this set for final compoundselection. We describe the validation of this approach by applyingit to the first BRD of BRD4. The selection and testing of 143 compoundslead to the discovery of six novel hits, including four unprecedentedKAc mimetics. We solved the crystal structure of four hits, determinedtheir binding mode, and improved their potency through synthesis andthe purchase of derivatives. This work provides a validated virtualscreening approach that is applicable to other BRDs and describesnovel KAc mimetics that can be further explored to design more potentinhibitors. [ABSTRACT FROM AUTHOR]