| Abstract
| - Losartan is the first recently approved drug against hypertension disease that competes withthe biological action of angiotensin II (AII) at the AT1 receptor. Its design was based on themimicry of the C-terminal segment of AII. Due to the biological significance of Losartan, itsstructure elucidation and conformational properties are reported as determined by NMRspectroscopy and computational analysis. In addition, molecular modeling of the peptideSarmesin [SarTyr(OMe)4AII], a competitive antagonist of AII, was also developed based onNMR and computational analysis data. Sarmesin's C-terminal was used as a template forsuperimposition with specific molecular features of interest in the structure of Losartan suchas the conformation of biphenyltetrazole, the n-butyl chain, and the orientation of hydroxymethylimidazole relative to the biphenyl template. The major conclusions derived from this studyare the following: (a) Sarmesin, like the AII superagonist [Sar1]AII, adopts a conformationwhich keeps in close proximity the key amino acids Sar1 (or Arg)-Tyr(OMe)4-His6-Phe8. (b)Losartan favors a low-energy conformation in which imidazole and tetrazole rings are placedin the opposite site relative to the spacer phenyl ring plane; the hydroxymethyl group is placedaway from the spacer phenyl ring, the alkyl chain is oriented above the spacer phenyl ring,and the two phenyl rings deviate approximately 60° from being coplanar. (c) Overlay of theC-terminal region of Sarmesin with Losartan using equivalent groups revealed an excellentmatch. (d) Interestingly, the matching between enantiomeric structures of Losartan was notequivalent, proposing that the chirality of this molecule is significant in order to exert itsbiological activity. These findings open a new avenue for synthetic chemists to design andsynthesize peptidomimetic drugs based on the C-terminal segment of the proposed model ofSarmesin. The new candidate drug molecules are not restricted to structurally resembleLosartan as the design is hitherto focused.
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