CRYSTALLOGRAPHIC STUDIES OF ANGIOTENSIN CONVERTING ENZYME-INHIBITORS AND ANALYSIS OF PREFERRED ZINC COORDINATION GEOMETRY

The molecular structures of two potent inhibitors of angiotensin converting enzyme (ACE, EC 3.4.15.1, dipeptidyl carboxypeptidase), ketoace, (5S)-5-benzamido-4-oxo-6-phenylhexanoyl-L-proline, and (1S,2r)-1-[[2-(benzoylthio)-cyclopentyl]carbonyl]-L-proline were determined by X-ray diffraction methods. The distances between the binding functions in both crystal structures are in agreement with the experimental results for the hypertension drug captopril and the enzyme substrate hippuryl-L-histidyl-L-leucine. The modified peptide skeletons of both inhibitors adopt extended conformations with the proline amide bond trans. Crystallographic data have been used to determine the coordination geometry for zinc—sulfhydryl and zinc-carbonyl interactions. Coordination distances and bond angles are found to be different from values assumed in models of the angiotensin converting enzyme active site. No preferred torsion angles for a zinc—sulfhydryl inhibitor interaction can be identified. Superposition of the crystallographic structures of four ACE ligands shows that the observed extended conformations place the phar-macophores, zinc atom ligand, carbonyl oxygen atom, and carboxyl group, in juxtaposition and provide an alternative model for the interaction of ligands with the ACE active site. © 1990, American Chemical Society. All rights reserved.