Discovery of novel inhibitors of Sortase A from Staphylococcus aureus by virtual screening

BIOL 207

Matthew L. Bentley, mbentley@mail.med.upenn.edu, Sarah E. Chobot, chobot@mail.med.upenn.edu, and Dewey G. McCafferty, deweym@mail.med.upenn.edu. Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 902 Stellar-Chance Labs, 422 Curie Blvd, Philadelphia, PA 19104-6059
The Sortase enzyme (SrtA) from Staphylococcus aureus plays an important role in the pathogenesis of infection, by anchoring virulence-associated proteins to the cell wall. Previous studies have shown that genetic knockouts of SrtA have a highly reduced capacity to form persistent infections in mammalian hosts. There is thus significant interest in developing SrtA inhibitors as potential therapeutics for Gram-positive infections. Towards this end, we have used DOCK-based virtual screening in conjunction with structure-driven design and inhibition studies to identify several novel classes of small molecule inhibitors of SrtA. Out of 643,959 virtual compounds screened, 371 exhibited DOCK scores of ≤ -31.50, and 27 of these compounds were tested for inhibition. Several of these compounds showed inhibition in vitro, with IC50s in the low-micromolar range. These compounds are being further characterized, and structural studies on the inhibited complex are being pursued to further guide inhibitor design and discovery efforts.
 

Enzymes
4:30 PM-6:30 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Biological Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006