The replacement of the cyano group (e.g. in 24) by fluorine (e.g. in 32 and 33) had no substantial effect on the binding mode, since both moieties were docked to occupy a similar position in the LHS subpocket (Figure ). Structurally related, high-affinity ligands for VHL have been reported both with a terminal fluorocyclopropyl and cyanocyclopropyl moiety, but the presence of neither a fluoro nor a cyano group reduced the affinity to VHL. In our docking approach, only a modest contribution to the overall binding was ascribed to the (S)-configured methyl group, which pointed away from the protein (Figure ). Based on the herein obtained FP results, most desmethyl derivatives were somewhat less potent VHL binders than their methylated counterparts (2, 26-29 versus 24, 30-33), a result being in accordance with other studies. However, certain VHL ligands with an unaltered benzylic position also possessed high affinity to VHL. These findings reflect the impact of structural plasticity of the target protein on ligand binding, which necessitates the tailored combination of structural features to optimize ligand affinity.