title: Identification of Novel Inhibitors of UDP-Galactopyranose Mutase by Structure-Based Virtual Screening.
abstract: UDP-galactopyranose mutase (UGM) is a flavo-enzyme involved in the bacterial cell wall biosynthesis. UGM catalyzes the reversible isomerization of UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf). UDP-Galf is the activated precursor of galactofuranose (Galf) residues that are essential components of the cell wall of certain pathogenic bacteria such as Klebsiella pneumoniae and Mycobacterium tuberculosis. Neither UGM nor Galf residues are found in humans, making Galf 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 IC50 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.
authors.affiliation: Department of Chemistry, University of Saskatchewa, 110 Science Place, Saskatoon, SK, Canada S7N 5C9.
authors.forename: Sarathy
authors.initials: S
authors.lastname: Karunan Partha
authors.affiliation: Centre for Biomolecular Sciences, School of Chemistry, The University of Nottingham, University Park, Nottingham, UK.
authors.forename: Ali
authors.initials: A
authors.lastname: Sadeghi-Khomami
authors.affiliation: Centre for Biomolecular Sciences, School of Chemistry, The University of Nottingham, University Park, Nottingham, UK.
authors.forename: Sylvaine
authors.initials: S
authors.lastname: Cren
authors.affiliation: Centre for Biomolecular Sciences, School of Chemistry, The University of Nottingham, University Park, Nottingham, UK.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Robinson
authors.affiliation: Centre for Biomolecular Sciences, School of Chemistry, The University of Nottingham, University Park, Nottingham, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Woodward
authors.affiliation: Department of Chemistry, University of Saskatchewa, 110 Science Place, Saskatoon, SK, Canada S7N 5C9.
authors.forename: Kate
authors.initials: K
authors.lastname: Slowski
authors.affiliation: Department of Chemistry, University of Saskatchewa, 110 Science Place, Saskatoon, SK, Canada S7N 5C9.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Berast
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Blake
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Centre for Biomolecular Sciences, School of Chemistry, The University of Nottingham, University Park, Nottingham, UK. neil.thomas@nottingham.ac.uk.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Thomas
authors.affiliation: Department of Chemistry, University of Saskatchewa, 110 Science Place, Saskatoon, SK, Canada S7N 5C9. david.sanders@usask.ca.
authors.forename: David A R
authors.initials: DA
authors.lastname: Sanders
keywords: Cell wall; Inhibitors; UDP-galactopyranose mutase