Investigating the Interaction of Cyclic RGD Peptidomimetics with α(V)β(6) Integrin by Biochemical and Molecular Docking Studies

The interaction of a small library of cyclic RGD (Arg-Gly-Asp) peptidomimetics with α(V)β(6) 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 α(V)β(6) 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 α(V)β(6) integrin. Although the RGD interaction with α(V)β(6) recapitulates the RGD binding mode observed in α(V)β(3), differences between the integrin binding pockets can strongly affect the ligand binding ability. In general, the peptidomimetics exhibited IC(50) values for integrin α(V)β(6) (i.e., the concentration of compound required for 50% inhibition of biotinylated fibronectin binding to isolated α(V)β(6) integrin) in the nanomolar range (77–345 nM), about 10–100 times higher than those for the related α(V)β(3) receptor, with a single notable ligand displaying a low nanomolar IC(50) 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.