Design, synthesis, functional and structural characterization of an inhibitor of N-acetylneuraminate-9-phosphate phosphatase: observation of extensive dynamics in an enzyme/inhibitor complex.
Bioorg Med Chem Lett
; 23(14): 4107-11, 2013 Jul 15.
Article
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| MEDLINE
| ID: mdl-23747226
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 11µM) in the range of the native substrate Neu5Ac-9-P (compound 1, Km 47µM). Combined SAR, modeling and NMR studies are consistent with the phosphonate group in inhibitor 3 forming a stable complex with native Mg(2+). 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 Ca(2+) and Mg(2+) are indicative of a highly dynamic process in the active site for the HDHD4/Mg(2+)/3 complex. Possible explanations for this observation are discussed.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Ácidos Siálicos
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Fosfatos de Azúcar
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Diseño de Fármacos
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Monoéster Fosfórico Hidrolasas
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Inhibidores Enzimáticos
Límite:
Animals
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Humans
Idioma:
En
Año:
2013
Tipo del documento:
Article