title: Discovery of Staphylococcus aureus sortase A inhibitors using virtual screening and the relaxed complex scheme.
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.
authors.affiliation: 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.
authors.forename: Albert H
authors.initials: AH
authors.lastname: Chan
authors.forename: Jeff
authors.initials: J
authors.lastname: Wereszczynski
authors.forename: Brendan R
authors.initials: BR
authors.lastname: Amer
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Yi
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jung
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.forename: Robert T
authors.initials: RT
authors.lastname: Clubb
mesh_terms: D019881:Aminoacyltransferases / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D013211:Staphylococcus aureus / Q000201:enzymology*
chemical_list: D001426:Bacterial Proteins; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases
keywords: Gram-positive; Staphylococcus aureus; docking; drug discovery; methicillin-resistant Staphylococcus aureus; molecular dynamics; relaxed complex scheme; sortase; sortase A; transpeptidation; virtual screening