Structure-activity relationships for the binding of ligands to xanthine or guanine phosphoribosyl-transferase from Toxoplasma gondii

Article abstract of DOI:10.1016/0006-2952(95)02070-5

Preliminary characterization of Toxoplasma gondii phosphoribosyltransferase activity towards purine nucleobases indicates that there are at least two enzymes present in these parasites. One enzyme uses hypoxanthine, guanine, and xanthine as substrates, while a second enzyme uses only adenine. Furthermore, competition experiments using the four possible substrates suggest that there may be a third enzyme that uses xanthine. Therefore, sixty-eight purine analogues and thirteen related derivatives were evaluated as ligands of T. gondii phosphoribosyltransferase, using xanthine or guanine as substrates, by examining their ability to inhibit these reactions in vitro. Inhibition was quantified by determining apparent K(i) values for compounds that inhibited these activities by greater than 10% at a concentration of 0.9 mM. On the basis of these data, a structure-activity relationship for the binding of ligands to these enzymes was formulated using hypoxanthine (6-oxopurine) as a reference compound. It was concluded that the following structural features of purine analogues are required or strongly preferred for binding to both enzymes: (1) a pyrrole-type nitrogen (lactam form) at the 1-position; (2) a methine (=CH-), a pyridine type nitrogen (=N-), or an exocyclic amino or oxo group at the 2-position; (3) no exocyclic substituents at the 3-position; (4) an exocyclic oxo or thio group in the one or thione tautomeric form at the 6-position; (5) a pyridine-type nitrogen (=N-) or a methine group at the 7-position; (6) a methine group at the 8-position; (7) a pyrrole-type nitrogen or a carbon at the 9-position; and (8) no exocyclic substituents at the 9-position. These findings provide the basis for the rational design of additional ligands of hypoxanthine, guanine, and xanthine phosphoribosyltransferase activities in T. gondii.