Moreover, the E M ED interaction energies (Fig. and Tab. S5 in SI) suggest that positioning of the substituted phenyl moieties as in the crystal structures of 2b and 2c with TbPTR1 is more energetically favorable than their I-derived configuration. Thus, the conformationally adaptable tails of 2b and 2c seem to be more optimally positioned in terms of halogenated phenyl interactions with subpocket C of TbPTR1 than the corresponding moiety of I. This observation could be exploited in further fragment-based compound design. SAR for different scaffolds informed by docking and crystallography. In the most favorable docking poses for 1b, we observe a similar binding pose as for 1a in the crystal structure -with 3,4-dichlorophenyl in subpocket D (Fig. , SI). However, despite a favorable docking score (Tab. S2, SI) and overall favorable van der Waals contacts (e.g., proximity to the Phe97 side chain), the N-cyclopropyl clashes slightly with the conserved water and it makes too close contact (heavy atoms within 3-Å distance) with the Cys168 side chain (see Fig. ). This could explain why adding N-cyclopropyl to the 1a scaffold in 1b does not improve binding affinity to TbPTR1 (IC 50 7.6 and 17.1 µM, respectively, see Tab. 2). A similar hypothesis can be made for V and its N-cyclopropyl-substituted variant 1c, a distinctly weaker binder of TbPTR1 than V (5.4 and 71.6 µM, respectively, see Tabs 1 and 2). In this case, the hydrophobic N-cyclopropyl makes contacts with hydrophobic Val206 (potentially favorable non-polar contact), but is also close to the nearby conserved water (potentially unfavorable), and interacts with the backbones of Gly205 and Ser207 (potentially unfavorable polar-non-polar contact, Fig. ). The contact with Gly205 may be too close (about 2.8 Å) to be resolved through the system conformational variability since it involves interactions with the protein backbone.