Novel cyclooxygenase-1 inhibitors discovered using affinity fingerprints

Journal of Medicinal Chemistry
Nancy HsuPaul Beroza

Abstract

We used protein affinity fingerprints to discover structurally novel inhibitors of cyclooxygenase-1 (COX-1) by screening a selected number of compounds, thus providing an alternative to extensive screening. From the affinity fingerprints of 19 known COX-1 inhibitors, a computational model for COX-1 inhibition was constructed and used to select candidate inhibitors from our compound library to be tested in the COX-1 assay. Subsequent refinement of the model by including affinity fingerprints of inactive compounds identified three molecules that were more potent than ibuprofen, a commonly used COX-1 inhibitor. These compounds are structurally distinct from those used to build the model and were discovered by testing only 62 library compounds. The discovery of these leads demonstrates the efficiency with which affinity fingerprints can identify novel bioactive chemotypes from known drugs.

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Citations

Dec 22, 2011·Journal of Medicinal Chemistry·Thibault VarinAnsgar Schuffenhauer
Oct 4, 2013·Journal of Medicinal Chemistry·László VégnerAndrás Málnási-Csizmadia
Dec 29, 2009·Journal of Biomedicine & Biotechnology·Yoshifumi Fukunishi, Haruki Nakamura
May 23, 2006·Drug Discovery Today·Steven E Hall
Jun 17, 2006·Journal of Molecular Graphics & Modelling·Yoshifumi FukunishiHaruki Nakamura
Jul 26, 2005·Trends in Biotechnology·Nicolas Froloff
Jan 1, 2010·Journal of Pest Science·Shana V StoddardRandy M Wadkins
Nov 6, 2015·Journal of Biomolecular Screening·Brice A P WilsonBarry R O'Keefe

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