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Titolo:
STRUCTURE-BASED DESIGN OF INHIBITORS OF PURINE NUCLEOSIDE PHOSPHORYLASE .4. A STUDY OF PHOSPHATE MIMICS
Autore:
GUIDA WC; ELLIOTT RD; THOMAS HJ; SECRIST JA; BABU YS; BUGG CE; ERION MD; EALICK SE; MONTGOMERY JA;
Indirizzi:
BIOCRYST PHARMACEUT INC,2190 PARKWAY LAKE DR BIRMINGHAM AL 35244 BIOCRYST PHARMACEUT INC BIRMINGHAM AL 35244 SO RES INST BIRMINGHAM AL 35255 CIBA GEIGY CORP,DIV PHARMACEUT SUMMIT NJ 07901 UNIV ALABAMA,CTR MACROMOLEC CRYSTALLOG BIRMINGHAM AL 35294
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 8, volume: 37, anno: 1994,
pagine: 1109 - 1114
SICI:
0022-2623(1994)37:8<1109:SDOIOP>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
14
Recensione:
Indirizzi per estratti:
Citazione:
W.C. Guida et al., "STRUCTURE-BASED DESIGN OF INHIBITORS OF PURINE NUCLEOSIDE PHOSPHORYLASE .4. A STUDY OF PHOSPHATE MIMICS", Journal of medicinal chemistry, 37(8), 1994, pp. 1109-1114

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 bindingsite, 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/10/20 alle ore 15:39:19