An effort to understand the molecular basis of hypertension through the study of conformational analysis of losartan and sarmesin using a combination of nuclear magnetic resonance spectroscopy and theoretical calculations.
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.
Mavromoustakos
T
T
Institute of Organic and Pharmaceutical Chemistry, The National Hellenic Research Foundation, Vas. Constantinou Ave. 48, 11635 Athens, Greece. tmavro@eie.gr
Kolocouris
A
A
Zervou
M
M
Roumelioti
P
P
Matsoukas
J
J
Weisemann
R
R
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000737:chemistry*; D006973:Hypertension / Q000209:etiology*; D019808:Losartan / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D011487:Protein Conformation
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D000804:Angiotensin II; C040420:angiotensin II, Sar(1)-Me-Tyr(4)-; D019808:Losartan