Losartan is the first recently approved
drug against
hypertension disease that competes with the
biological action of
angiotensin II (AII) at the AT1 receptor. Its design was based on the mimicry of the C-terminal segment of AII. Due to the
biological significance of
Losartan, its structure elucidation and conformational properties are reported as determined by NMR spectroscopy and computational analysis. In addition, molecular modeling of the
peptide Sarmesin [Sar1Tyr(OMe)4AII], a competitive antagonist of AII, was also developed based on NMR and computational analysis data.
Sarmesin's C-terminal was used as a template for superimposition with specific molecular features of interest in the structure of
Losartan such as the conformation of biphenyltetrazole, the n-butyl chain, and the orientation of hydroxymethylimidazole relative to the
biphenyl template. The major conclusions derived from this study are the following: (a)
Sarmesin, like the AII superagonist [Sar1]AII, adopts a conformation which keeps in close proximity the key
amino acids Sar1 (or Arg2)-Tyr(OMe)4-His6-Phe8. (b)
Losartan favors a low-energy conformation in which
imidazole and
tetrazole rings are placed in the opposite site relative to the spacer phenyl ring plane; the hydroxymethyl group is placed away from the spacer phenyl ring, the alkyl chain is oriented above the spacer phenyl ring, and the two phenyl rings deviate approximately 60 degrees from being coplanar. (c) Overlay of the C-terminal region of
Sarmesin with
Losartan using equivalent groups revealed an excellent match. (d) Interestingly, the matching between enantiomeric structures of
Losartan was not equivalent, proposing that the chirality of this molecule is significant in order to exert its
biological activity. These findings open a new avenue for synthetic chemists to design and synthesize
peptidomimetic drugs based on the C-terminal segment of the proposed model of
Sarmesin. The new candidate
drug molecules are not restricted to structurally resemble
Losartan as the design is hitherto focused.