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Bisson C, Britton KL, Sedelnikova SE, et al. Mirror-Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide. Angew Chem Int Ed Engl. 2016;55(43):13485-13489doi: 10.1002/anie.201607185.
Bisson, C., Britton, K. L., Sedelnikova, S. E., Rodgers, H. F., Eadsforth, T. C., Viner, R. C., Hawkes, T. R., Baker, P. J., & Rice, D. W. (2016). Mirror-Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide. Angewandte Chemie (International ed. in English), 55(43), 13485-13489. https://doi.org/10.1002/anie.201607185
Bisson, Claudine, et al. "Mirror-Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide." Angewandte Chemie (International ed. in English) vol. 55,43 (2016): 13485-13489. doi: https://doi.org/10.1002/anie.201607185
Bisson C, Britton KL, Sedelnikova SE, Rodgers HF, Eadsforth TC, Viner RC, Hawkes TR, Baker PJ, Rice DW. Mirror-Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide. Angew Chem Int Ed Engl. 2016 Oct 17;55(43):13485-13489. doi: 10.1002/anie.201607185. Epub 2016 Sep 26. PMID: 27717128; PMCID: PMC5113775.
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Angew Chem Int Ed Engl. 2016 Oct 17;55(43):13485-13489. doi: 10.1002/anie.201607185. Epub 2016 Sep 26.

Mirror-Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide.

Angewandte Chemie (International ed. in English)

Claudine Bisson, K Linda Britton, Svetlana E Sedelnikova, H Fiona Rodgers, Thomas C Eadsforth, Russell C Viner, Tim R Hawkes, Patrick J Baker, David W Rice

Affiliations

  1. Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK.
  2. Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, University of Dundee, Dundee, DD1 5EH, UK.
  3. Syngenta, Jealott's Hill International Research Station, Bracknell, RG42 6EY, UK.
  4. Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK. [email protected].
  5. Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK. [email protected].

PMID: 27717128 PMCID: PMC5113775 DOI: 10.1002/anie.201607185

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.

© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Keywords: chirality; drug design; enantioselectivity; inhibitors; structural biology

References

  1. Acta Crystallogr D Biol Crystallogr. 2013 Dec;69(Pt 12):2461-7 - PubMed
  2. Nature. 2000 Feb 10;403(6770):614-5 - PubMed
  3. Nat Rev Drug Discov. 2012 Dec;11(12):972-3 - PubMed
  4. J Comput Chem. 2004 Oct;25(13):1605-12 - PubMed
  5. Eur J Clin Pharmacol. 1984;26(6):663-8 - PubMed
  6. Plant Physiol. 1995 Mar;107(3):719-723 - PubMed
  7. Molecules. 2015 Jan 12;20(1):1088-103 - PubMed
  8. Int J Biomed Sci. 2006 Jun;2(2):85-100 - PubMed
  9. Arch Biochem Biophys. 1965 Dec;112(3):544-7 - PubMed
  10. Arch Biochem Biophys. 2003 Jun 1;414(1):1-12 - PubMed
  11. Arch Biochem Biophys. 1981 Oct 15;211(2):564-74 - PubMed
  12. Structure. 2015 Jul 7;23(7):1236-45 - PubMed
  13. Chem Biol. 2005 Apr;12(4):427-37 - PubMed
  14. Biochemistry. 1991 Jun 18;30(24):6024-31 - PubMed
  15. Biochem J. 1995 Mar 1;306 ( Pt 2):385-97 - PubMed

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