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Discovery of S taphylococcus aureus Sortase A Inhibitors Using Virtual Screening and the Relaxed Complex Scheme
Author(s) -
Chan Albert H.,
Wereszczynski Jeff,
Amer Brendan R.,
Yi Sung Wook,
Jung Michael E.,
McCammon J. Andrew,
Clubb Robert T.
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12167
Subject(s) - sortase a , staphylococcus aureus , virtual screening , sortase , docking (animal) , microbiology and biotechnology , virulence , chemistry , computational biology , methicillin resistant staphylococcus aureus , antibiotics , drug discovery , biology , biochemistry , bacteria , medicine , genetics , gene , nursing
Staphylococcus aureus is the leading cause of hospital‐acquired infections in the U nited S tates. 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‐1 H ‐perimidine scaffold is particularly promising, and its binding mechanism was further investigated using molecular dynamics simulations and conducting preliminary structure–activity relationship studies.