Comparative target/off-target mapping and docking studies support design focused on selective multitarget inhibition To develop enhanced selective inhibitors of the parasite targets, we employed a multitargetbased design approach to improve inhibition of TbPTR1, TbDHFR, LmPTR1 and LmDHFR, while retaining low hDHFR off-target inhibition. The next generation of pteridine-like compounds was created by dissecting the part of 1b attached to the pteridine core into three modules. These were: N10, the substitution to the N10 position; PABA, the para-amino benzoic acid (PABA) moiety; and Tail, the cyclic glutamate tail (Figure ). We separately modified each of these modules to obtain three new series of compounds. The modifications of each module were based on binding mode predictions from docking in the different targets and the off-target hDHFR and our previously published optimization guidelines for MTX-like scaffolds. The key concepts adopted in the compound design are summarized in Figure .