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J Med Chem. 2016 Jun 9;59(11):5248-63. doi: 10.1021/acs.jmedchem.6b00002. Epub 2016 Apr 26.

Structural Basis for the Selective Binding of Inhibitors to 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from Staphylococcus aureus and Escherichia coli.

Author information

1
Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
2
CSIRO Biosciences Program , Parkville, Victoria 3052, Australia.
3
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University , Nanjing 210093, People's Republic of China.

Abstract

6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a member of the folate biosynthesis pathway found in prokaryotes and lower eukaryotes that catalyzes the pyrophosphoryl transfer from the ATP cofactor to a 6-hydroxymethyl-7,8-dihydropterin substrate. We report the chemical synthesis of a series of S-functionalized 8-mercaptoguanine (8MG) analogues as substrate site inhibitors of HPPK and quantify binding against the E. coli and S. aureus enzymes (EcHPPK and SaHPPK). The results demonstrate that analogues incorporating acetophenone-based substituents have comparable affinities for both enzymes. Preferential binding of benzyl-substituted 8MG derivatives to SaHPPK was reconciled when a cryptic pocket unique to SaHPPK was revealed by X-ray crystallography. Differential chemical shift perturbation analysis confirmed this to be a common mode of binding for this series to SaHPPK. One compound (41) displayed binding affinities of 120 nM and 1.76 μM for SaHPPK and EcHPPK, respectively, and represents a lead for the development of more potent and selective inhibitors of SaHPPK.

PMID:
27094768
DOI:
10.1021/acs.jmedchem.6b00002
[Indexed for MEDLINE]

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