Structure-based, split-pool synthesis was used to discover non-peptide binding elements for the leucine-proline binding pocket of the Src SH3 domain. Binding characteristics of the protein pocket were then explored by comparing a series of ligands that contains subtle variants of the parent non-peptide binding structure. Further insights into this receptor-ligand interaction were provided by multidimensional NMR structure determination of one of the non-peptide ligands.