Analysis of the active conformation of angiotensin II: a comparison of AII and non-peptide AII antagonists

Several molecular models of angiotensin II (AII) were constructed using information derived primarily from conformationally constrained AII analogues. In order to refine the original models, AII was compared using computer-aided molecular graphics with several of the recently reported non-peptide AII antagonists. As a first approximation, the imidazole, phenyl ring and acidic moiety (i.e., carboxyl, tetrazole) of the non-peptide AII antagonists were overlapped with the corresponding features of the peptide. AII and Dup 753 were overlapped using Multifit (SYBYL) and then both were optimized individually and refit; this procedure was repeated three times to generate a working model of AII. The less-potent non-peptide AII antagonists S 8308 and Exp 6155 could also be overlaid with the model of AII, albeit not as well as DuP 753. The working model of AII, which has a twisted U-shape, places the imidazole of His6 and the terminal carboxylate approximately 8.7 A apart.