Molecular modeling of the complex of endothelin-1(ET-1) with the endothelin type A (ETA) receptor and the rational design of a peptide antagonist

ET-1 is the most potent vasoconstrictor known to date, causing vasoconstriction when bound to the ETA receptor. Inhibitors of the binding of ET-I to the ETA receptor would be of immense value as potential therapeutic agents in the treatment of cardiovascular disorders such as angina and hypertension. We present here the rational design of such an inhibitor, which is arrived at on the basis of a model of theET-1/ ETA receptor complex proposed by us. The model is found to be consistent with binding and mutagenesis studies of ET-I as well as of BQ123, a known, potent ETA-selective antagonist which competes with ET-1 for receptor binding. BQ123 is a peptidic antagonist which is constrained to adopt a definite conformation on account of its cyclic nature, The noncyclic peptide antagonist designed by us also has a unique conformation because it contains two dehydro-Alanine (Delta Ala) residues which, on account of their planarity, cause the peptide backbone to bend in a specific and predictable manner. The folding rules for peptides containing Delta Ala were derived in our earlier studies. Energy minimization and modelling of the complex of the designed peptide with the ETA receptor indicate that the antagonist is ETA-selective and the binding is more stable and more specific as compared to that of BQ123.