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Identification of Novel Inhibitors of UDP‐Galactopyranose Mutase by Structure‐Based Virtual Screening
Author(s) -
Karunan Partha Sarathy,
SadeghiKhomami Ali,
Cren Sylvaine,
Robinson Richard I.,
Woodward Simon,
Slowski Kate,
Berast Lindsey,
Zheng Blake,
Thomas Neil R.,
Sanders David A. R.
Publication year - 2011
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201100085
Subject(s) - mutase , in silico , escherichia coli , virtual screening , enzyme , docking (animal) , biochemistry , klebsiella pneumoniae , dehydratase , chemistry , mycobacterium tuberculosis , biology , klebsiella pneumonia , stereochemistry , drug discovery , tuberculosis , medicine , nursing , pathology , gene
UDP‐galactopyranose mutase (UGM) is a flavo‐enzyme involved in the bacterial cell wall biosynthesis. UGM catalyzes the reversible isomerization of UDP‐galactopyranose (UDP‐Gal p ) to UDP‐galactofuranose (UDP‐Gal f ). UDP‐Gal f is the activated precursor of galactofuranose (Gal f ) residues that are essential components of the cell wall of certain pathogenic bacteria such as Klebsiella pneumoniae and Mycobacterium tuberculosis . Neither UGM nor Gal f residues are found in humans, making Gal f biosynthesis a potential drug target for developing antibacterial agents. We report the identification of novel inhibitors of UGM by in silico docking of the LeadQuest compound database against UGM from Escherichia coli . The 13 most promising inhibitors were then evaluated against K. pneumonia and M. tuberculosis UGMs by enzyme inhibition studies. Two inhibitors were identified with IC 50 values of ∼1 µM and subsequently these compounds were docked into the recently solved X‐ray structure of Deinococcus radiodurans UGM. The structure‐activity relationships of the initial 13 compounds evaluated as inhibitors are discussed.