of Work: Molecular modeling comprised of molecular dynamics, conformational searching and superimpositions with crystal structures were used to propose a delta-opioid antagonist pharmacophore and to assess the tertiary structure of the delta opioid agonist deltorphin. The study on deltorphins were conducted in order to induce structural changes in peptides in which unsual amino acids are substituted for their natural cognate, such as Aib and or aminocycloalkanes, to limit their inherent flexibility. Conformational changes were detected by 1-H NMR (using COSY, NOESY, HOHAHA, ROESY, DQF-COSY experiments) and CD under variying solvent and temperature conditions. The aromatic ring distance may be an important characteristic of delta antagonists to provide a receptor-bound conformation. The 3-D structure of H-Dmt-Tic- OH contains a cis peptide bond, gauche+ orientation of the Tic side chain, a near parallel orientation and close proximity of 5.4 A between the aromatic rings. The topographical features observed with the Dmt- Tic pharmacophore differentiate if from all other peptides. The data suggest that the presumed receptor-bound conformation involves a sandwich arrangement betweent the Dmt and Tic aromatic rings. This was confirmed by X-ray diffraction analyese on N,N(dimethyl)Dmt-Tic-OH. In fact, the small intraring distance of delta-opioid antagonists differs from the extended intramolecular distances of aromatic rings (11-12 A) found for delta, and mu antagonists as well as mu agonists. Molecular modeling continues to delineate differences between delta and mu antagonists and how their structure is compatible with proposed receptor binding sites. Small peptide analogues with dual receptor binding characteristics or selectivity for the mu opioid receptor will assist in applying molecular modeling in a predictive mode. In fact, analysis of a new opioid agonist with a weak delta antagonist activity suggests that the concept of message and address domains must be modified: the linear sequence of the peptide may not be the correct determinant to verify the amino acid residue side chains involved in these recognition sites. Thus, our delta- and mu-opioid antagonist and agonist pharmacophores will serve as scaffolds to design new potent ligands. - Molecular modeling; molecular dynamics; Monte Carlo; conformational searching; low energy conformers; petptide structure.
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