Resumen
The interaction of a small library of cyclic RGD (Arg-Gly-Asp) peptidomimetics with aVß6 integrin has been investigated by means of competitive solid phase binding assays to the isolated receptor and docking calculations in the crystal structure of the aVß6 binding site. To this aim, a rigid receptor-flexible ligand docking protocol has been set up and then applied to predict the binding mode of the cyclic RGD peptidomimetics to aVß6 integrin. Although the RGD interaction with aVß6 recapitulates the RGD binding mode observed in aVß3, differences between the integrin binding pockets can strongly affect the ligand binding ability. In general, the peptidomimetics exhibited IC50 values for integrin aVß6 (i.e., the concentration of compound required for 50% inhibition of biotinylated fibronectin binding to isolated aVß6 integrin) in the nanomolar range (77?345 nM), about 10?100 times higher than those for the related aVß3 receptor, with a single notable ligand displaying a low nanomolar IC50 value (2.3 nM). Insights from the properties of the binding pocket combined with the analysis of the docking poses provided a rationale for ligand recognition and selectivity.