Fibrin represents a suitable target for addressing delivery systems loaded by fibrinolytic drugs. Selective ligands capable to recognize fibrin could be used as targeting moieties for such systems. In this study the interactions between the gamma(312-324) epitope of human fibrin and peptidic ligands were analyzed by using experimental and computational methods. Binding free energies were calculated through the molecular mechanics/generalized born surface area approach. Good qualitative agreements between the experimental and calculated data were obtained. The binding affinity seems to be well correlated (R(2)=0.69) with the changes of the nonpolar solvation energy term computed from solvent-accessible surface area calculation. These results indicate that current methods of estimating binding free energies are efficient for achieving information on protein-ligand interactions.