Small and colorful stones make beautiful mosaics: Fragment-based chemogenomics

Research output: Contribution to journalJournal articleResearchpeer-review

  • Chris De Graaf
  • Henry F. Vischer
  • Gerdien E. De Kloe
  • Kooistra, Albert Jelke
  • Saskia Nijmeijer
  • Martien Kuijer
  • Mark H.P. Verheij
  • Paul J. England
  • Jacqueline E. Van Muijlwijk-Koezen
  • Rob Leurs
  • Iwan J.P. De Esch

Smaller stones with a wide variety of colors make a higher resolution mosaic. In much the same way, smaller chemical entities that are structurally diverse are better able to interrogate protein binding sites. This feature article describes the construction of a diverse fragment library and an analysis of the screening of six representative protein targets belonging to three diverse target classes (G protein-coupled receptors ADRB2, H1R, H3R, and H4R, the ligand-gated ion channel 5-HT 3R, and the kinase PKA) using chemogenomics approaches. The integration of experimentally determined bioaffinity profiles across related and unrelated protein targets and chemogenomics analysis of fragment binding and protein structure allow the identification of: (i) unexpected similarities and differences in ligand binding properties, and (ii) subtle ligand affinity and selectivity cliffs. With a wealth of fragment screening data being generated in industry and academia, such approaches will contribute to a more detailed structural understanding of ligand-protein interactions.

Original languageEnglish
JournalDrug Discovery Today
Issue number7-8
Pages (from-to)323-330
Number of pages8
Publication statusPublished - 1 Apr 2013
Externally publishedYes

ID: 199376511