Discovery of Staphylococcus aureus Sortase A Inhibitors Using Virtual Screening and the Relaxed Complex Scheme

Authors

  • Albert H. Chan,

    1. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA
    2. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA
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  • Jeff Wereszczynski,

    1. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA
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  • Brendan R. Amer,

    1. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA
    2. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA
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  • Sung Wook Yi,

    1. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA
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  • Michael E. Jung,

    1. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA
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  • J. Andrew McCammon,

    1. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA
    2. Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA
    3. Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA
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  • Robert T. Clubb

    Corresponding author
    1. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA
    2. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA
    3. UCLA-Department of Energy Institute for Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA, USA
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  • The copyright line for this article was changed on 10th April, 2015 after original online publication.

Abstract

Staphylococcus aureus is the leading cause of hospital-acquired infections in the United States. The emergence of multidrug-resistant strains of S. aureus has created an urgent need for new antibiotics. Staphylococcus aureus uses the sortase A enzyme to display surface virulence factors suggesting that compounds that inhibit its activity will function as potent anti-infective agents. Here, we report the identification of several inhibitors of sortase A using virtual screening methods that employ the relaxed complex scheme, an advanced computer-docking methodology that accounts for protein receptor flexibility. Experimental testing validates that several compounds identified in the screen inhibit the activity of sortase A. A lead compound based on the 2-phenyl-2,3-dihydro-1H-perimidine scaffold is particularly promising, and its binding mechanism was further investigated using molecular dynamics simulations and conducting preliminary structure–activity relationship studies.

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