ANALYSES OF LIGAND-BINDING IN 5 ENDOTHIAPEPSIN CRYSTAL COMPLEXES AND THEIR USE IN THE DESIGN AND EVALUATION OF NOVEL RENIN INHIBITORS

Five renin inhibitors were cocrystallized with endothiapepsin, a funga l enzyme homologous to renin. Crystal structures of inhibitor-bound co mplexes have provided invaluable insight regarding the three-dimension al structure of the aspartic proteinase family of enzymes, as well as the steric and polar interactions that occur between the proteins and the bound ligands. Beyond this, subtleties of binding have been reveal ed, including multiple subsite binding modes and subsite interdependen cies. This information has been applied in the design of novel potent renin inhibitors and in the understanding of structure-activity relati onships and enzyme selectivities.