PhotoAffinity Bits: A Photoaffinity-Based Fragment Screening Platform for Efficient Identification of Protein Ligands.

Advances in genomic analyses enable the identification ofnew proteins that are associated with disease. To validate these targets, toolmolecules are required to demonstrate that a ligand can have adisease-modifying effect. Currently, as tools are reported for only a fractionof the proteome, platforms for ligand discovery are essential to leverageinsights from genomic analyses. Fragment screening offers an efficient approachto explore chemical space, however, it remains challenging to develop techniquesthat are both sufficiently high-throughput and sensitive. We present a fragmentscreening platform, termed PhABits (PhotoAffinity Bits), which utilises alibrary of photoreactive fragments to covalently capture fragment-proteininteractions. Hits can be profiled to determine potency and site ofcrosslinking, and subsequently developed as reporters in a competitivedisplacement assay to identify novel hit matter. We envision that the PhABitswill be widely applicable to novel protein targets, identifying starting pointsin the development of therapeutics.