The structures of several pharmaceutically important enzymes have recently been solved by X-ray crystallography and important advances have been made in protein homology model building. A method for rational drug design using these targets is proposed. In Phase I, information contained in known, high resolution protein structures is used to assess the preferred packing arrangement of each of the twenty amino acids. Using this information, individual residues in the active site of a target enzyme will be optimally packed with residues found, from the database analysis, to be preferred by these amino acids.Acceptably packed residues will be linked into designed, optimally packed peptide ligands of the site. These modeled peptides may then form the basis of a drug design effort based on their sequence and conformation. The location of sidechains of the modeled peptide will be used to generate pharmacophore maps to be used in the search for small molecule, non-peptide inhibitors. In Phase II, we intend to use this drug design approach to design novel drugs directed at serine proteases of the coagulation cascade.Heart attacks and related thrombotic disorders are a leading cause of death and there is a recognized need for specific inhibitors of several of the enzymes involved that may serve as effective therapies.