Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10591483 | Bioorganic & Medicinal Chemistry Letters | 2013 | 5 Pages |
Abstract
The design, synthesis and characterization of a phosphonate inhibitor of N-acetylneuraminate-9-phosphate phosphatase (HDHD4) is described. Compound 3, where the substrate C-9 oxygen was replaced with a nonlabile CH2 group, inhibits HDHD4 with a binding affinity (IC50 11 μM) in the range of the native substrate Neu5Ac-9-P (compound 1, Km 47 μM). Combined SAR, modeling and NMR studies are consistent with the phosphonate group in inhibitor 3 forming a stable complex with native Mg2+. In addition to this key interaction, the C-1 carboxylate of the sugar interacts with a cluster of basic residues, K141, R104 and R72. Comparative NMR studies of compounds 3 and 1 with Ca2+ and Mg2+ are indicative of a highly dynamic process in the active site for the HDHD4/Mg2+/3 complex. Possible explanations for this observation are discussed.
Keywords
Related Topics
Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Soong-Hoon Kim, Keith L. Constantine, Gerald J. Duke, Valentina Goldfarb, John T. Hunt, Stephen Johnson, Kevin Kish, Herbert E. Klei, Patricia A. McDonnell, William J. Metzler, Luciano Mueller, Michael A. Poss, Craig R. Fairchild, Rajeev S. Bhide,