In the complexes with 2b and 2d, the linker is in the trans configuration, with its amide oxygen pointing towards the substrate loop, and the tail phenyl ring is located inside subpocket C (Fig. ). In this orientation, the meta-halogen on the phenyl moiety (either a chlorine in 2b or a bromine in 2d) forms a halogen bond with the backbone carbonyl of Trp221, similarly as for I (Fig. ). However, the other three compounds crystallized with TbPTR1, sharing a para-halogen (either a chlorine in 1a and 2c or a bromine in 2e), have the amide linker in the cis-configuration with the phenyl moiety occupying subpocket D at the entrance of the catalytic cavity (Fig. ). Notably, one of the top two predicted binding modes of 1a is consistent with the crystallographically resolved binding mode in TbPTR1 (compare Figs and), with the exception of the orientation of the amide bond (which however does not directly interact with the receptor and probably depends on the water network that cannot be fully reproduced in classical docking simulations).