Understanding the three-dimensional aspects of drug-receptor interactions and their specificity at the molecular level has become a focal point in modern drug discovery. Herein, we describe a set of methods by which the binding site on a protein can be located and mapped and the protein-ligand intermolecular interactions can be studied in the context of drug discovery. The methodology we describe is based on the empirical Hydropathic INTeraction (HINT) force field. Applications of the novel cavity detection algorithm, VICE, are demonstrated in delineating the binding pockets. The binding site environment is mapped using hydropathic "complementary map." The two binding sites are compared by calculating their 3D differences and the intermolecular interactions between a bound ligand and protein was further studied by HINT intermolecular maps. We illustrate the applications of these different types of HINT maps through an example from the development of selective COX-2 inhibitors.