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Design of substrate-site-directed inhibitors of adenylate kinase and hexokinase. Effect of substrate substituents on affinity on affinity for the adenine nucleotide sites.

Abstract：

:Nineteen derivatives of adenosine 5'-phosphate (AMP) bearing acylaminomethyl, acetoxy, or alkylaminomethyl substituents on the phosphate-ribose bridge (5' and O-5' positions) of AMP together with 2',3'-O-ethylidene, 2',3',-O-isopropylidene, and 2',3'-di-O-acetyl derivatives of AMP have been synthesized. Their substrate and/or competitive inhibitor properties with pig rabbit muscle AMP kinases indicate that all the substituents except 2',3'-O-ethlidene with the pig enzyme permitted binding of AMP at its enzymic site. Determination of enzyme-inhibitor dissociation constants showed that several compounds with substituents on the ribose-phosphate bridge bind as well or better than AMP. The affinity is ascribed in part to interaction between substituents and a lipophilic region of the enzymes adjacent to the ribose-phosphate bridge in the enzyme-AMP complexes. The enzyme-inhibitor dissociation constants reveal a structural dissimilarity between the pig and rabbit enzymes in the vicinity of the lipophilic region. The substrate and inhibitor properties of eight ATP derivatives gave evidence that affinity of ATP for its substrate site on the AMP kinases is compatible with acetyl- or chloroacetylaminomethyl groups at the phosphate-ribose bridge or with 2',3'-O-ethylidene or isopropylidene residues. The yeast hexokinase-ATP complex tolerated an acetylaminomethyl group at C-5' or a benzoylaminomethyl group adjacent to O-5'. The present findings regarding substituent tolerance could be used in the design of adenine nucleotide site-directed irreversible inhibitors.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Hampton A,Slotin LA,Kappler F,Sasaki T,Perini F

doi

10.1021/jm00234a004

subject

Has Abstract

pub_date

1976-12-01 00:00:00

pages

1371-7

issue

12

eissn

0022-2623

issn

1520-4804

journal_volume

19

pub_type

杂志文章

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