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 pharmacophores, 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.