The lack of inhibition by compound 2, even when restrained to the binding pocket, may relate to its reduced interactions with F280, which has been suggested to be part of the allosteric network of PTP1B . Compound 1 wraps around the side chain and π stacks via its thiazole moiety, forcing F280 to adopt primarily an "up" rotamer (Figure and Figure , magenta χ 1 angle ca. -60 deg.).