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

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.

DOI: 10.1002/anie.201607185

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Cite this paper

@inproceedings{Bisson2016MirrorImagePP, title={Mirror‐Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide}, author={Claudine Bisson and K Linda Britton and Svetlana E. Sedelnikova and H Fiona Rodgers and Thomas C. Eadsforth and Russell C. Viner and Tim R Hawkes and Patrick J Baker and David W. Rice}, booktitle={Angewandte Chemie}, year={2016} }