Fragment screening on Staphylococcus aureus HPPK - A folate pathway target

Sandeep Chhabra, Olan Dolezal, Meghan Hattarki, Thomas Peat, Jamie Scott Simpson, James David Swarbrick

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2 Citations (Scopus)


An NMR-based screen of a commercially available fragment library was performed on the folate pathway antimicrobial target, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus (SaHPPK). Initial 1D saturation transfer difference-NMR screening resulted in an impractically high hit rate (43 ), which advocated the use of a strategy based on 2D (SOFAST) N-15 HMQC NMR experiments. Chemical shift perturbations were used to identify, validate, and map the location of 16 initial binders (hit rate of 2 ). Fourteen compounds were purchased based on an identified thioamide pharmacophore. Binding affinities (K-d) were measured by surface plasmon resonance, revealing a modest improvement in potency over the initial 16 hits, with the best fragment found to bind to the apo enzyme with a K-d of 420 mu M, corresponding to a ligand efficiency of 1.8kJ/heavy atom. Four fragments identified represent useful starting points for the generation of leads that may ultimately be developed into new antimicrobial agents.
Original languageEnglish
Pages (from-to)1537 - 1543
Number of pages7
JournalAustralian Journal of Chemistry
Issue number12
Publication statusPublished - 2013

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