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.
Original language | English |
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Pages (from-to) | 13485-13489 |
Number of pages | 5 |
Journal | Angewandte Chemie International Edition |
Volume | 55 |
Issue number | 43 |
Early online date | 26 Sept 2016 |
DOIs | |
Publication status | Published - 17 Oct 2016 |
Keywords
- chirality
- drug design
- enantioselectivity
- inhibitors
- structural biology