Investigating the interaction of cyclic RGD peptidomimetics with αVβ6integrin by biochemical and molecular docking studies

The interaction of a small library of cyclic RGD (Arg-Gly-Asp) peptidomimetics with αVβ6integrin has been investigated by means of competitive solid phase binding assays to the isolated receptor and docking calculations in the crystal structure of the αVβ6binding 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 αVβ6integrin. Although the RGD interaction with αVβ6recapitulates the RGD binding mode observed in αVβ3, differences between the integrin binding pockets can strongly affect the ligand binding ability. In general, the peptidomimetics exhibited IC50values for integrin αVβ6(i.e., the concentration of compound required for 50% inhibition of biotinylated fibronectin binding to isolated αVβ6integrin) in the nanomolar range (77–345 nM), about 10–100 times higher than those for the related αVβ3receptor, with a single notable ligand displaying a low nanomolar IC50value (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.