This study showed that small, lipophilic folate analogs AG337 and AG331, optimized to bind human thymidylate synthase (TS) at low nanomolar concentrations, bound Plasmodium TS 130-fold more weakly.Based on thermodn. principles, it should be possible to identify reciprocal small mols. that bind Plasmodium TS better than human TS.Data suggest that species-specific inhibitor design may be realized by exploiting subtle host-parasite differences in enzyme active-site conformations that are dictated by distant amino acids in the proteins.It is proposed that, in the absence of folate-derivatives, human and Plasmodium TS active sites exist in slightly different ground-state conformations.Upon meeting the full-length 5,10-methylenetetrahydrofolate substrate, or the full size inhibitor 1843U89, favorable interactions could provide sufficient intrinsic binding energy to both change the conformation of the enzymes to the catalytically active form and still maintain effective enzyme inhibition.