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Labeled Ligand Displacement: Extending NMR-Based Screening of Protein Targets
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    Labeled Ligand Displacement: Extending NMR-Based Screening of Protein Targets
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    Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064
    *To whom correspondence should be addressed. E-mail: [email protected]
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2010, 1, 6, 295–299
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    https://doi.org/10.1021/ml1000849
    Published June 24, 2010
    Copyright © 2010 American Chemical Society

    Abstract

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    NMR spectroscopy has enjoyed widespread success as a method for screening protein targets, especially in the area of fragment-based drug discovery. However, current methods for NMR-based screening all suffer certain limitations. Two-dimensional methods like “SAR by NMR” require isotopically labeled protein and are limited to proteins less than about 50 kDa. For one-dimensional, ligand-based methods, results can be confounded by nonspecific compound binding, resonance overlap, or the need for a special NMR probe. We present here a ligand-based method that relies on the exchange broadening observed for a 13C-labeled molecule upon binding to a protein target (labeled ligand displacement). This method can be used to screen both individual compounds and mixtures and is free of the artifacts inherent in other ligand-based methods.

    Copyright © 2010 American Chemical Society

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    Supporting Information

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    Experimental procedures along with two figures showing the exchange-broadening effect for a 13C-labeled peptide bound to the protein Bcl-xL and for 13C-labeled ATP bound to Hsp90 and two tables that show the amount of signal recovered upon addition of competing ligands for both Hsp90 and carbonic anhydrase. This material is available free of charge via the Internet at http://pubs.acs.org.

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    This article is cited by 12 publications.

    1. Ivanhoe K. H. Leung, Marina Demetriades, Adam P. Hardy, Clarisse Lejeune, Tristan J. Smart, Andrea Szöllössi, Akane Kawamura, Christopher J. Schofield, and Timothy D. W. Claridge . Reporter Ligand NMR Screening Method for 2-Oxoglutarate Oxygenase Inhibitors. Journal of Medicinal Chemistry 2013, 56 (2) , 547-555. https://doi.org/10.1021/jm301583m
    2. Yanhu Wei, Paul J. Wesson, Igor Kourkine, and Bartosz A. Grzybowski. Measurement of Protein−Ligand Binding Constants from Reaction-Diffusion Concentration Profiles. Analytical Chemistry 2010, 82 (21) , 8780-8784. https://doi.org/10.1021/ac102055a
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    4. Timothy D.W. Claridge. Protein–Ligand Screening by NMR. 2016, 421-455. https://doi.org/10.1016/B978-0-08-099986-9.00011-7
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    7. Adam J. Plaunt, Kasey J. Clear, Bradley D. Smith. 19 F NMR indicator displacement assay using a synthetic receptor with appended paramagnetic relaxation agent. Chem. Commun. 2014, 50 (72) , 10499-10501. https://doi.org/10.1039/C4CC04159C
    8. Bernd Beck, Michael Bieler, Peter Haebel, Andreas Teckentrup, Alexander Weber, Nils Weskamp. APPLICATIONS OF CHEMINFORMATICS IN PHARMACEUTICAL RESEARCH. 2013, 291-320. https://doi.org/10.1002/9781118742785.ch13
    9. Susan M. Boyd, Andrew P. Turnbull, Björn Walse. Fragment library design considerations. WIREs Computational Molecular Science 2012, 2 (6) , 868-885. https://doi.org/10.1002/wcms.1098
    10. Laurel O. Sillerud, Richard S. Larson. Advances in Nuclear Magnetic Resonance for Drug Discovery. 2012, 195-266. https://doi.org/10.1007/978-1-61779-965-5_10
    11. Renaldo Mendoza, Andrew M. Petros, Yaya Liu, Rama Thimmapaya, Carol S. Surowy, Walter F. Leise, Ana Pereda-Lopez, Sanjay C. Panchal, Chaohong Sun. Cracking the molecular weight barrier: Fragment screening of an aminotransferase using an NMR-based functional assay. Bioorganic & Medicinal Chemistry Letters 2011, 21 (18) , 5248-5250. https://doi.org/10.1016/j.bmcl.2011.07.039
    12. Christopher A. Lepre. Practical Aspects of NMR-Based Fragment Screening. 2011, 219-239. https://doi.org/10.1016/B978-0-12-381274-2.00009-1

    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2010, 1, 6, 295–299
    Click to copy citationCitation copied!
    https://doi.org/10.1021/ml1000849
    Published June 24, 2010
    Copyright © 2010 American Chemical Society

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