NMR study of cyclic peptides with renin inhibitor activity

Abstract

Several cyclic analogues of renin inhibitors, based on Glu- D -Phe-Lys motif have been investigated by NMR spectroscopy and molecular dynamics calculations (MD). The 15 membered macrocycle, resulting from Glu and Lys side-chain cyclization, exhibits conformational preference. The structural evidence from NMR shows the presence of hydrogen bond between Lys NH and Glu side-chain carbonyl, resulting in a 10 membered pseudo β-turn-like structure. The structure of the cyclic moiety is similar in all the peptides, which takes at least two conformations around Cα-Cβ in Glu side chain. The restrained MD calculations further support such observations and show that the macrocycle is fairly rigid, with two conformations about the Glu Cα-Cβ bond. The linear peptide appendages, which are essential for activity in cyclic peptides, show an extended structure in the β-region of Ramchandran plot. These calculations also demonstrate that for the most active peptide, two major conformers each exist about the Cα-CO bond of the Lys, D-Trp and Leu residues. In this peptide, the cyclic moiety presents a negatively charged surface formed due to the carbonyl oxygens, which are thus available to form hydrogen bonds with the receptor. The linear fragment presents further binding sites with a surface which has the hydrophobic side chains of D-Trp, Leu and D-Met on one side and carbonyls on the other side.