Selectivity of drug targeting is necessary in order to forestall undesired side-effects. Here, we examine the structural grounds for the configuration-dependent selectivity of 2,7-bis(4-amidinobenzylidene)-cycloheptan-1-one (1) for factor Xa and trypsin: Previous studies showed that factor Xa is preferentially inhibited by the (Z,Z) configuration isomer of (1), whilst trypsin binds equally well to both (E,Z) and (Z,Z) forms. Using engineered trypsin variants, we find similar overall binding modes for the (E,Z) and (Z,Z) isomers. Minor changes in van der Waals' contacts to Tyr99 (Leu in trypsin) explain the differential inhibition of factor Xa. We note differences in the experimental electron densities observed from co-crystallisation and soaking experiments: while the co-crystallisation of (1) with variants containing Tyr99 (Leu99) reveal the exclusive presence of the (Z,Z) ((E,Z)) configurations respectively, soaking experiments with either variant result in mixtures of (E,Z), (Z,Z) and (E,E). This discrepancy arises presumably from differences in the spatial (packing considerations) or chemical (crystallisation conditions) microenvironments. The results presented here represent an extreme example of the problems that face structure-based drug design, in particular the dangers inherent in relying on a single crystal structure for interpreting protein-ligand interactions.