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Chem Biol Drug Des. 2013 Oct;82(4):418-28. doi: 10.1111/cbdd.12167.

Discovery of Staphylococcus aureus sortase A inhibitors using virtual screening and the relaxed complex scheme.

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Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.


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.


Gram-positive; Staphylococcus aureus; docking; drug discovery; methicillin-resistant Staphylococcus aureus; molecular dynamics; relaxed complex scheme; sortase; sortase A; transpeptidation; virtual screening

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