Structure-based design of inhibitors of purine nucleoside phosphorylase. 4. A study of phosphate mimics.
J Med Chem
; 37(8): 1109-14, 1994 Apr 15.
Article
en En
| MEDLINE
| ID: mdl-8164252
ABSTRACT
9-(3,3-Dimethyl-5-phosphonopentyl)guanine was synthesized and found to be a potent inhibitor of purine nucleoside phosphorylase (PNP) (IC50 = 44 nM). A number of other functional end groups were investigated as phosphate mimics attached to the 9-position of guanine by this same alkyl side chain, which provided a sensitive method for the detection of any interaction of these groups with the phosphate binding site of PNP. Both the sulfonic acid (compound 13) and the carboxylic acid (compound 15) end groups interact significantly with the phosphate binding site, but in different ways, as determined by X-ray crystallographic analysis of the complexes. The sulfonic acid of 13, which binds about one-fourth as tightly as the phosphonate 12, binds in the phosphate subsite much like the phosphonic acid. The carboxylic acid, the interaction of which is much weaker, turns away from the center of the phosphate binding site to form hydrogen bonds with Ser 200 and Met 219. Thus, the only phosphate mimics that bind like phosphate itself are themselves highly ionic, probably with limited ability to penetrate cell membranes.
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Banco de datos:
MEDLINE
Asunto principal:
Fosfatos
/
Purina-Nucleósido Fosforilasa
/
Guanina
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1994
Tipo del documento:
Article