Moreover, our exploration of halogen substituents showed that the singly halogenated compounds are slightly more active on TbPTR1 than the doubly halogenated compounds, though the magnitude of the effect is small in the context of drug design. Consistently with the QM data, the substituents at the meta position of the phenyl ring in the analyzed scaffolds were found to be slightly energetically more favorable for both anti-TbPTR1 and anti-LmPTR1 activity. Although the effect on the PTR1 activity is small, it is consistent for different halogen substitients at the para/meta positions, and for both TbPTR1 and LmPTR1 (Tab. 2), showing surprising sensitivity of the QM method. Unfortunately, removing para-chlorine from the doubly-chlorinated 1a phenyl also significantly reduced the low micromolar anti-parasite activity. The predictions of the QM calculations were confirmed by the crystallographic data, and showed that the position of the halogen substituents affected the positioning of the flexible halogenated phenyl tails in subpocket C vs. D. Overall, the data provide insights into the halogen interactions with PTR1, although the halogen substitutions do not play a dominant role in the anti-PTR1 activities. The approach used here may be useful for other ligand series, in particular, where halogens have a greater effect on compound activity.