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

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  • Title:
    Mirror-Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide
  • Author: 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.
  • Description: 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.
  • Identifier: ISSN: 0044-8249
  • Creation Date: 2016

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