Design,synthesis, functional and structural characterization of an inhibitor of N-acetylneuraminate-9-phosphate phosphatase: Observation of extensive dynamics in an enzyme/inhibitor complex |
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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 |
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Institution: | Bristol-Myers Squibb Research and Development, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA |
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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. |
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Keywords: | Inhibitor Comparative NMR studies Enzyme/inhibitor complex |
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