Chan, Albert H.; Wereszczynski, Jeff; Amer, Brendan R.; Yi, Sung Wook; Jung, Michael E.; McCammon, J. Andrew; Clubb, Robert T.
Discovery of Staphylococcus aureus Sortase A Inhibitors Using Virtual Screening and the Relaxed Complex Scheme
CHEMICAL BIOLOGY & DRUG DESIGN, 82:418-428, OCT 2013

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.

DOI:10.1111/cbdd.12167

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