Small and colorful stones make beautiful mosaics: Fragment-based chemogenomics
Research output: Contribution to journal › Journal article › Research › peer-review
Chris De Graaf, Henry F. Vischer, Gerdien E. De Kloe, Albert J. Kooistra, 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.
|Journal||Drug Discovery Today|
|Number of pages||8|
|Publication status||Published - 1 Apr 2013|