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

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• 作者：Dr. Claudine Bisson ; Dr. K. Linda Britton ; Dr. Svetlana E. Sedelnikova ; H. Fiona Rodgers ; Dr. Thomas C. Eadsforth ; Dr. Russell C. Viner ; Dr. Tim R. Hawkes ; Dr. Patrick J. Baker and Prof. David W. Rice
• 刊名：Angewandte Chemie
• 出版年：2016
• 出版时间：October 17, 2016
• 年：2016
• 卷：128
• 期：43
• 页码：13683-13687
• 全文大小：1732K
• ISSN：1521-3757

文摘

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.