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Identification of a New Zinc Binding Chemotype by Fragment Screening

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Griffith University, Griffith Institute for Drug Discovery, Nathan, Brisbane, Queensland 4111, Australia
CSIRO, Biomedical Manufacturing Program, 343 Royal Parade, Parkville, Melbourne, Victoria 3052, Australia
*S.-A.P. Tel: +61 7 3735 7825. E-mail: [email protected]
*T.S.P. Tel: +61 3 9662 7304. E-mail: [email protected]
Cite this: J. Med. Chem. 2017, 60, 17, 7333–7349
Publication Date (Web):August 17, 2017
Copyright © 2017 American Chemical Society

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    Abstract Image

    The discovery of a new zinc binding chemotype from screening a nonbiased fragment library is reported. Using the orthogonal fragment screening methods of native state mass spectrometry and surface plasmon resonance a 3-unsubstituted 2,4-oxazolidinedione fragment was found to have low micromolar binding affinity to the zinc metalloenzyme carbonic anhydrase II (CA II). This affinity approached that of fragment sized primary benzenesulfonamides, the classical zinc binding group found in most CA II inhibitors. Protein X-ray crystallography established that 3-unsubstituted 2,4-oxazolidinediones bound to CA II via an interaction of the acidic ring nitrogen with the CA II active site zinc, as well as two hydrogen bonds between the oxazolidinedione ring oxygen and the CA II protein backbone. Furthermore, 3-unsubstituted 2,4-oxazolidinediones appear to be a viable starting point for the development of an alternative class of CA inhibitor, wherein the medicinal chemistry pedigree of primary sulfonamides has dominated for several decades.

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b00606.

    • Data collection and structure refinement statistics of fragment–hCA II crystal structures, NMR spectra, SPR sensorgrams for compounds, and calculated properties for selected compounds (PDF)

    • Molecular formula strings for compounds (CSV)

    Accession Codes

    All of the coordinates and structure factors have been deposited in the PDB and are available with the following codes: 5TXY, 5TY8, 5TY9, 5TYA, 5U0D, 5U0E, 5U0F, 5U0G, 5VGY. Authors will release the atomic coordinates and experimental data upon article publication.

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