Mirror-image packing provides a molecular basis for the nanomolar equipotency of enantiomers of an experimental herbicide

Claudine Bisson, K. Linda Britton, Svetlana E. Sedelnikova, H. Fiona Rodgers, Thomas C. Eadsforth, Russell C. Viner, Tim R. Hawkes, Patrick J. Baker (Lead / Corresponding author), David W. Rice (Lead / Corresponding author)

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Abstract

Programs of drug discovery generally exploit one enantiomer of a chiral compound for lead development following the principle that enantiomer recognition is central to biological specificity. However, chiral promiscuity has been identified for a number of enzyme families, which have shown that mirror-image packing can enable opposite enantiomers to be accommodated in an enzyme's active site. Reported here is a series of crystallographic studies of complexes between an enzyme and a potent experimental herbicide whose chiral center forms an essential part of the inhibitor pharmacophore. Initial studies with a racemate at 1.85 Å resolution failed to identify the chirality of the bound inhibitor, however, by extending the resolution to 1.1 Å and by analyzing high-resolution complexes with the enantiopure compounds, we determined that both enantiomers make equivalent pseudosymmetric interactions in the active site, thus mimicking an achiral reaction intermediate.

Original languageEnglish
Pages (from-to)13485-13489
Number of pages5
JournalAngewandte Chemie International Edition
Volume55
Issue number43
Early online date26 Sep 2016
DOIs
Publication statusPublished - 17 Oct 2016

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Enantiomers
Herbicides
Mirrors
Enzymes
Reaction intermediates
Chirality
Lead

Keywords

  • chirality
  • drug design
  • enantioselectivity
  • inhibitors
  • structural biology

Cite this

Bisson, C., Britton, K. L., Sedelnikova, S. E., Rodgers, H. F., Eadsforth, T. C., Viner, R. C., ... Rice, D. W. (2016). Mirror-image packing provides a molecular basis for the nanomolar equipotency of enantiomers of an experimental herbicide. Angewandte Chemie International Edition, 55(43), 13485-13489. https://doi.org/10.1002/anie.201607185
Bisson, Claudine ; Britton, K. Linda ; Sedelnikova, Svetlana E. ; Rodgers, H. Fiona ; Eadsforth, Thomas C. ; Viner, Russell C. ; Hawkes, Tim R. ; Baker, Patrick J. ; Rice, David W. / Mirror-image packing provides a molecular basis for the nanomolar equipotency of enantiomers of an experimental herbicide. In: Angewandte Chemie International Edition. 2016 ; Vol. 55, No. 43. pp. 13485-13489.
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abstract = "Programs of drug discovery generally exploit one enantiomer of a chiral compound for lead development following the principle that enantiomer recognition is central to biological specificity. However, chiral promiscuity has been identified for a number of enzyme families, which have shown that mirror-image packing can enable opposite enantiomers to be accommodated in an enzyme's active site. Reported here is a series of crystallographic studies of complexes between an enzyme and a potent experimental herbicide whose chiral center forms an essential part of the inhibitor pharmacophore. Initial studies with a racemate at 1.85 {\AA} resolution failed to identify the chirality of the bound inhibitor, however, by extending the resolution to 1.1 {\AA} and by analyzing high-resolution complexes with the enantiopure compounds, we determined that both enantiomers make equivalent pseudosymmetric interactions in the active site, thus mimicking an achiral reaction intermediate.",
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Bisson, C, Britton, KL, Sedelnikova, SE, Rodgers, HF, Eadsforth, TC, Viner, RC, Hawkes, TR, Baker, PJ & Rice, DW 2016, 'Mirror-image packing provides a molecular basis for the nanomolar equipotency of enantiomers of an experimental herbicide', Angewandte Chemie International Edition, vol. 55, no. 43, pp. 13485-13489. https://doi.org/10.1002/anie.201607185

Mirror-image packing provides a molecular basis for the nanomolar equipotency of enantiomers of an experimental herbicide. / Bisson, Claudine; Britton, K. Linda; Sedelnikova, Svetlana E.; Rodgers, H. Fiona; Eadsforth, Thomas C.; Viner, Russell C.; Hawkes, Tim R.; Baker, Patrick J. (Lead / Corresponding author); Rice, David W. (Lead / Corresponding author).

In: Angewandte Chemie International Edition, Vol. 55, No. 43, 17.10.2016, p. 13485-13489.

Research output: Contribution to journalArticle

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T1 - Mirror-image packing provides a molecular basis for the nanomolar equipotency of enantiomers of an experimental herbicide

AU - Bisson, Claudine

AU - Britton, K. Linda

AU - Sedelnikova, Svetlana E.

AU - Rodgers, H. Fiona

AU - Eadsforth, Thomas C.

AU - Viner, Russell C.

AU - Hawkes, Tim R.

AU - Baker, Patrick J.

AU - Rice, David W.

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PY - 2016/10/17

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N2 - Programs of drug discovery generally exploit one enantiomer of a chiral compound for lead development following the principle that enantiomer recognition is central to biological specificity. However, chiral promiscuity has been identified for a number of enzyme families, which have shown that mirror-image packing can enable opposite enantiomers to be accommodated in an enzyme's active site. Reported here is a series of crystallographic studies of complexes between an enzyme and a potent experimental herbicide whose chiral center forms an essential part of the inhibitor pharmacophore. Initial studies with a racemate at 1.85 Å resolution failed to identify the chirality of the bound inhibitor, however, by extending the resolution to 1.1 Å and by analyzing high-resolution complexes with the enantiopure compounds, we determined that both enantiomers make equivalent pseudosymmetric interactions in the active site, thus mimicking an achiral reaction intermediate.

AB - Programs of drug discovery generally exploit one enantiomer of a chiral compound for lead development following the principle that enantiomer recognition is central to biological specificity. However, chiral promiscuity has been identified for a number of enzyme families, which have shown that mirror-image packing can enable opposite enantiomers to be accommodated in an enzyme's active site. Reported here is a series of crystallographic studies of complexes between an enzyme and a potent experimental herbicide whose chiral center forms an essential part of the inhibitor pharmacophore. Initial studies with a racemate at 1.85 Å resolution failed to identify the chirality of the bound inhibitor, however, by extending the resolution to 1.1 Å and by analyzing high-resolution complexes with the enantiopure compounds, we determined that both enantiomers make equivalent pseudosymmetric interactions in the active site, thus mimicking an achiral reaction intermediate.

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