A number of groups have reported on the successful design of inhibitors directed against trypanosomal (2, 4, 15-16), leishmanial (6), malarial (19), and tritrichomonal (3, 27) targets active in the 10 n M to 50 μM range. Due to a lack of interconversion between the two purine nucleotide pools, either of the two enzymes could serve as a potential target for giardiasis chemotherapy (33).
A combination of structure-based scaffold selection using virtual library screening across the PRT gene family and solid phase library synthesis led to identification of smaller (molecular weight, parasites. , an anaerobic binucleate flagellated protozoan that causes intestinal infection, a condition termed giardiasis in mammals (1), relies primarily on two independent pathways for its nucleotide synthesis.
As a second step in this process, altering the phthalimide moiety to optimize interactions in the guanine-binding pocket of GPRT is expected to lead to compounds with promising activity against Computer-aided drug design in combination with combinatorial chemistry approaches, whereby focused or diverse combinatorial libraries can be designed using computational methods, is becoming increasingly important in the process of drug discovery for parasitic targets (7, 11). Adenine PRT and guanine PRT (GPRT) catalyze the synthesis of AMP and GMP, respectively.
Evaluation of binding preferences for combinatorial libraries across a range of targets could, in principle, provide information about scaffold generality or selectivity as related to the target selection (M. The unusual substitution is observed at the bottom of the purine binding site, with Tyr127 taking the place of the typically well-conserved Ile or Leu residue.
All protozoan parasites lack the ability to synthesize purine nucleotides de novo.
Another structural difference can be noted in the position of the conserved Lys residue, which has been shown to interact with exocyclic O6 of the purine in all of the known structures of purine PRTs.