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

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

doi:10.1016/j.drudis.2012.12.003

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

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^*

^*Corresponding author af dette arbejde

25 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Drug Discovery Today
Vol/bind	18
Udgave nummer	7-8
Sider (fra-til)	323-330
Antal sider	8
ISSN	1359-6446
DOI	https://doi.org/10.1016/j.drudis.2012.12.003
Status	Udgivet - 1 apr. 2013
Udgivet eksternt	Ja

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abstract = "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.",

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AU - Kooistra, Albert J.

AU - Nijmeijer, Saskia

AU - Kuijer, Martien

AU - Verheij, Mark H.P.

AU - England, Paul J.

AU - Van Muijlwijk-Koezen, Jacqueline E.

AU - Leurs, Rob

AU - De Esch, Iwan J.P.

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

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