NMR study of cyclic peptides with renin inhibitor activity.
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 beta-turn-like structure. The structure of the cyclic moiety is similar in all the peptides, which takes at least two conformations around Calpha-Cbeta 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 Calpha-Cbeta bond. The linear peptide appendages, which are essential for activity in cyclic peptides, show an extended structure in the beta-region of Ramchandran plot. These calculations also demonstrate that for the most active peptide, two major conformers each exist about the Calpha-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.
Sarma
A V S
AV
Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007, India.
Ramana Rao
M H V
MH
Sarma
J A R P
JA
Nagaraj
R
R
Dutta
A S
AS
Kunwar
A C
AC
D002942:Circular Dichroism; D003198:Computer Simulation; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008956:Models, Chemical; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry*; D011487:Protein Conformation; D000092502:Renin Inhibitors
D010456:Peptides, Cyclic; D000092502:Renin Inhibitors