The occupancies of exogenous ligands were individually adjusted to values resulting in atomic displacement parameters comparable to those of surrounding protein atoms in fully occupied sites. The final models were checked with Coot and Procheck. Statistics for data refinement are reported in Table . Figures were generated using TbPTR1, TbDHFR, LmPTR1, LmDHFR, hDHFR and hTS target/off-target enzyme assays. Computational docking studies. Docking studies were performed using a rigid receptor in Glide standard precision (SP) and extra precision (XP) modes and employing the Induced Fit (IF) protocol to allow for refinement of binding site residues. For rigid receptor docking, van der Waals radii scaling of ligand atoms and settings for sampling, addition of Epik state penalties to the docking score, rewarding of intramolecular hydrogen bonds and enhancement of the planarity of conjugated π-groups were chosen as described previously , but a total of 50 poses per ligand were subjected to post-docking energy minimization. For the in silico library, we used SP docking with a constraint on all heavy atoms of the pteridine core to match the orientation of MTX in the corresponding protein receptor with a tolerance of 1 Å.