The identification of ligand binding sites on a protein is an essential step in the selection of inhibitors of protein-ligand or protein-protein interactions via virtual database screening. To facilitate binding site identification, a novel descriptor, the binding response, is proposed in the present paper to quantitatively evaluate putative binding sites on the basis of their response to a test set of probe compounds. The binding response is determined on the basis of contributions from both the ligand-protein interaction energy and the geometry of binding poses for a database of test ligands. A favorable binding response is obtained for binding sites with favorable ligand binding energies and with ligand geometries within the putative site for the majority of compounds in the test set. The utility of this descriptor is illustrated by applying it to a number of known protein-ligand complexes, showing the approach to identify the experimental binding sites as the highest scoring site in 26 out of 29 cases; in the remaining three cases, it was among the top three scoring sites. This method is combined with sphere-based site identification and clustering methods to yield an automated approach for the identification of binding sites on proteins suitable for database screen or de novo drug design.