Evaluating the Advantages of Using 3D-Enriched Fragments for Targeting BET Bromodomains.

ABSTRACT: Fragment-based ligand discovery has been successful in targeting diverse proteins. Despite drug-like molecules having more 3D character, traditional fragment libraries are largely composed of flat, aromatic fragments. The use of 3D-enriched fragments for enhancing library diversity is underexplored especially against protein-protein interactions. Here, we evaluate using 3D-enriched fragments against bromodomains. Bromodomains are highly ligandable, but selectivity remains challenging, particularly for bromodomain and extraterminal (BET) family bromodomains. We screened a 3D-enriched fragment library against BRD4(D1) via ¹H CPMG NMR with a protein-observed ¹⁹F NMR secondary assay. The screen led to 29% of the hits that are selective over two related bromodomains, BRDT(

SUBMITTER: Johnson JA 

PROVIDER: S-EPMC6912871 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature