Structural basis for the selective binding of inhibitors to 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus and Escherichia coli

Matthew L. Dennis, Noel P. Pitcher, Michael D. Lee, Aaron J. Debono, Zhong-Chang Wang, Jitendra R. Harjani, Raphaël Rahmani, Ben Cleary, Thomas S. Peat, Jonathan B. Baell, James D. Swarbrick

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)5248-5263
Number of pages16
JournalJournal of Medicinal Chemistry
Volume59
Issue number11
DOIs
Publication statusPublished - 9 Jun 2016

Cite this

Dennis, Matthew L. ; Pitcher, Noel P. ; Lee, Michael D. ; Debono, Aaron J. ; Wang, Zhong-Chang ; Harjani, Jitendra R. ; Rahmani, Raphaël ; Cleary, Ben ; Peat, Thomas S. ; Baell, Jonathan B. ; Swarbrick, James D. / Structural basis for the selective binding of inhibitors to 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus and Escherichia coli. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 11. pp. 5248-5263.
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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.",
author = "Dennis, {Matthew L.} and Pitcher, {Noel P.} and Lee, {Michael D.} and Debono, {Aaron J.} and Zhong-Chang Wang and Harjani, {Jitendra R.} and Rapha{\"e}l Rahmani and Ben Cleary and Peat, {Thomas S.} and Baell, {Jonathan B.} and Swarbrick, {James D.}",
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Structural basis for the selective binding of inhibitors to 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus and Escherichia coli. / Dennis, Matthew L.; Pitcher, Noel P.; Lee, Michael D.; Debono, Aaron J.; Wang, Zhong-Chang; Harjani, Jitendra R.; Rahmani, Raphaël; Cleary, Ben; Peat, Thomas S.; Baell, Jonathan B.; Swarbrick, James D.

In: Journal of Medicinal Chemistry, Vol. 59, No. 11, 09.06.2016, p. 5248-5263.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Structural basis for the selective binding of inhibitors to 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus and Escherichia coli

AU - Dennis, Matthew L.

AU - Pitcher, Noel P.

AU - Lee, Michael D.

AU - Debono, Aaron J.

AU - Wang, Zhong-Chang

AU - Harjani, Jitendra R.

AU - Rahmani, Raphaël

AU - Cleary, Ben

AU - Peat, Thomas S.

AU - Baell, Jonathan B.

AU - Swarbrick, James D.

PY - 2016/6/9

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N2 - 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.

AB - 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.

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