Conformational study of a potent human renin inhibitor: X-ray crystal structure of isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-{N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naphthyl)propionyl]-L-histidylamino}butyrate (KRI-1314), a pentapeptide analogue with amino acid sequence corresponding to the cleavage site of angiotensinogen

Abstract

A potent inhibitor of renin, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-{N-[(2R)-2-morpholino-carbonylmethyl-3-(1-naphthyl)propionyl]-L-histidylamino}butyrate (KRI-1314), was crystallized as a cinnamic acid salt. The crystal structure of KRI-1314 was determined by X-ray analysis, and the conformation is discussed in relation to the inhibitory activity. The backbone chain of the molecule was largely twisted at the unusual amino acid residue of cyclohexylnorstatine. The observed conformation was compared with that of the model pentapeptide corresponding to the scissile site of angiotensinogen. The stacking interaction was formed between the histidine side-chains related by the crystallographic 2-fold screw axis. The histidine imidazole rings were further fixed by hydrogen bonds with the cinnamic acid. The water molecule of crystallization mediated the hydrogen-bonding bridge of the cinnamic acid with the hydroxy oxygen of the cyclohexylnorstatine. Such interactions appear to be very important in considerations of inhibitor-or substrate-binding mechanisms against renin.