A photoaffinity-based fragment screening platform for efficient identification of protein ligands

Emma K. Grant, David J. Fallon, Michael M. Hann, Ken G. M. Fantom, Chad Quinn, Francesca Zappacosta, Roland S. Annan, Chun-wa Chung, Paul Bamborough, David P. Dixon, Peter Stacey, David House, Vipulkumar K. Patel, Nick C. O. Tomkinson, Jacob T. Bush

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease‐modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space. Presented here is a fragment‐screening platform, termed PhABits (PhotoAffinity Bits), which utilizes a library of photoreactive fragments to covalently capture fragment–protein interactions. Hits can be profiled to determine potency and the site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. The PhABit platform is envisioned to be widely applicable to novel protein targets, identifying starting points in the development of therapeutics.
Original languageEnglish
Pages (from-to)21096-21105
Number of pages10
JournalAngewandte Chemie International Edition
Volume59
Issue number47
Early online date3 Aug 2020
DOIs
Publication statusPublished - 16 Nov 2020

Keywords

  • genomic analyses
  • PhotoAffinity Bits
  • PhABits
  • novel protein targets

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