Taken together, alterations to the PABA moiety, due to its central location in the compound scaffold, different pocket sizes and surrounding residue patterns in targets (Figure ), display highly variable effects on the activity profiles. of 4c and 4d can form more extended hydrophobic interactions with Phe31 of hDHFR than with the corresponding methionine in the parasite DHFR variants (Figure ). In the parasite protein, moreover, Asn64 in the pocket entrance of hDHFR is replaced by phenylalanine, which, upon interaction with the compound tail, becomes solvent-exposed.