Structure-activity relationship for the binding of nucleoside ligands to adenosine kinase from Toxoplasma gondii.
Biochem Pharmacol
; 49(10): 1501-12, 1995 May 17.
Article
in En
| MEDLINE
| ID: mdl-7763293
One hundred and twenty-eight purine nucleoside analogs were evaluated as ligands of Toxoplasma gondii adenosine kinase (EC 2.7.1.20) by examining their ability to inhibit this enzyme in vitro. Inhibition was quantified by determining apparent Ki (appKi) values for those compounds that inhibited this enzyme by greater than 10% at a concentration of 1 mM. Two compounds, N6-(p-methoxybenzoyl)adenosine and 7-iodo-7-deazaadenosine (iodotubercidin), were found to bind to the enzyme (appKi = 3.9 and 1.6 microM, respectively) better than adenosine. On the basis of these data, a structure-activity relationship for the binding of ligands to T. gondii adenosine kinase was formulated using adenosine as a reference compound. It was concluded that the following structural features of purine nucleoside analogs are required or strongly preferred for binding: (1) "pyridine-type" endocyclic nitrogens at the 1- and 3-positions; (2) an exocyclic hydrogen at the 2-position; (3) 6-position exocyclic substituents in the lactim tautomeric form; (4) a "pyridine-type" endocyclic nitrogen at the 7-position or hydrophobic exocyclic substituents attached to an endocyclic carbon at the 7-position; (5) an endocyclic methine or "pyridine-type" nitrogen at the 8-position; (6) an endocyclic nitrogen at the 9-position; (7) a pentose or "pentose-like" (e.g. hydroxylated cyclopentene) moiety attached to the 9-position nitrogen; (8) hydroxyl groups at the 2'- and 3'-positions in a ribose configuration; (9) a hydroxymethyl or methyl (i.e. 5'-deoxy) group at the 5'-position; (10) a beta-D-nucleoside configuration; and (11) an anti conformation around the N-glycosidic bond. In addition, there appears to be a "pocket" in the catalytic site of T. gondii adenosine kinase, adjacent to the 6-position of adenosine, that can accommodate large (preferably unsaturated or aromatic) substituents (e.g. phenyl). These findings provide the basis for the rational design of additional ligands of T. gondii adenosine kinase.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Purine Nucleosides
/
Toxoplasma
/
Adenosine Kinase
/
Antiprotozoal Agents
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Biochem Pharmacol
Year:
1995
Document type:
Article
Affiliation country:
United States
Country of publication:
United kingdom