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- Title
Mirror-Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide.
- Authors
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.
- 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.
- Subjects
HERBICIDES; ENANTIOMERS analysis; CHIRAL stationary phases; ENZYMES; CHIRALITY
- Publication
Angewandte Chemie, 2016, Vol 128, Issue 43, p13683
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201607185