Synthesis, molecular modelling, and NMR structure determination of four cyclic peptide antagonists of endothelin.
A combined distance geometry and molecular mechanics/dynamics (MM/MD) protocol was unable to predict the active conformation of the cyclic pentapeptide inhibitor of endothelin-1 receptor, BQ-123, and two analogues. However, the MM/MD method alone is sufficient to predict the solution conformation of a third analogue. In that one case, the combination of proline at residue 3 and an N alpha-methyl substitution at residue 5 provides enough internal constraints to eliminate conformational flexibility seen in the other three analogues. For this constrained analogue, the 50 lowest energy conformations (out of a set of 500 DGEOM-generated, MM/MD minimized conformations) differ by no more than 3.9 kcal/mol. Thirty three of these 50 conformations have backbone atom RMSDs of less than 0.33 A, relative to the lowest energy conformation. The accuracy of this MM/MD model is verified by determining the solution structure of each of the four analogues with 2D NMR techniques. Each of the cyclic pentapeptides has a well defined solution conformation where a proline residue is clearly in a gamma-turn, leaving the remaining residues in a loose beta-turn. All four experimental NMR conformations agree closely with the MM/MD model.
Bradley
E K
EK
Chiron Corporation, Emeryville, CA 94608.
Ng
S C
SC
Simon
R J
RJ
Spellmeyer
D C
DC
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D065128:Endothelin Receptor Antagonists; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D013816:Thermodynamics
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic