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Mirror‐Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide
Author(s) -
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.
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201607185
Subject(s) - enantiomer , enantiopure drug , pharmacophore , chirality (physics) , chemistry , stereochemistry , resolution (logic) , enantioselective synthesis , active site , combinatorial chemistry , enzyme , organic chemistry , computer science , physics , chiral symmetry breaking , nambu–jona lasinio model , quantum mechanics , artificial intelligence , quark , catalysis
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.