Protein-protein interaction inhibitor discovery has proven difficult due to the large surface area and dynamic interfaces.  To facilitate the early lead discovery rate, we describe a rapid protein-based <sup>19</sup>F NMR method for detecting protein-ligand interactions by screening low complexity molecules (fragments) as well as higher complexity molecules.  We label the aromatic amino acids with the highly sensitive fluorine atom, due to the high conservation of aromatic residues at protein interfaces and have tested the sensitivity, accuracy, and speed of this method with the protein interaction domain of CBP, KIX, screening 508 small molecule fragments. Experiments can be carried out in less than five minutes. We have extended our method to bromodomains including Brd4, BrdT and BPTF. Selective bromodomain ligands can be challenging to design.  To address this challenge, we have elaborated on our approach for simultaneously testing multiple bromodomains in the same experiment. These studies have led to the discovery of some of the first selective ligands for the bromodomain BPTF and new submicromolar ligands for Brd4. The speed, ease of interpretation, and low concentration of protein needed for binding experiments affords a new method to discover and characterize both native and new ligands for bromodomains and may find utility in the study of additional epigenetic “reader” domains.

Fluorinated bromodomains: Choosing the right halogen for small molecule discovery

251st National Meeting (2016)

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