<p>We discuss methods and ideas of virtual screening (VS) for drug discovery by examining the performance of VS-APPLE, a recently developed VS method, which extensively utilizes the tendency of single binding pockets to bind diversely different ligands, i.e. promiscuity of binding pockets. In VS-APPLE, multiple ligands bound to a pocket are spatially arranged by maximizing structural overlap of the protein while keeping their relative position and orientation with respect to the pocket surface, which are then combined into a multiple-ligand template for screening test compounds. To greatly reduce the computational cost, comparison of test compound structures are made only with limited regions of the multiple-ligand template. Even when we use the narrow regions with most densely populated atoms for the comparison, VS-APPLE outperforms other conventional VS methods in terms of Area Under the Curve (AUC) measure. This region with densely populated atoms corresponds to the consensus region among multiple ligands. It is typically observed that expansion of the sampled region including more atoms improves screening efficiency. However, for some target proteins, considering only a small consensus region is enough for the effective screening of test compounds. These results suggest that the performance test of VS methods sheds light on the mechanisms of protein-ligand interactions, and elucidation of the protein-ligand interactions should further help improvement of VS methods.</p>