Topological similarities between a cyclic enkephalin analogue and a potent opiate alkaloid: a computer-modeling approach.

The cyclic enkephalin analogue H-Tyr-cyclo[-D-N delta-Orn-Gly-Phe-Leu-] (1-c) and the rigid narcotic alkaloid 7 alpha-[(1R)-1-hydroxy-1-methyl-3-phenylpropyl]-6,14- endo-ethenotetrahydrooripavine (PEO) were studied by using computer graphics methods to investigate potential geometrical congruencies of their respective pharmacophoric elements. Particular emphasis was placed on the relative spatial disposition of the tyramine moiety and the additional aromatic ring that occurs in both molecules. A three-dimensional vector map was generated defining the locus of the C21 aromatic ring for all those conformers of PEO having up to 10 kcal above the minimum energy conformer. A systematic conformational search on the cyclic peptide afforded four allowable sets of conformers whose side chain of the phenylalanine residue coincided with the vector map of PEO. Local energy minima for the peptide within the revised mutual vector space were found and subjected to bimolecular energy refinement with correspondingly local energy minima for the opiate alkaloid. Several low-energy conformers of the cyclic peptide were identified that permitted a good fit with the alkaloid provided that the tyramine moiety of the respective molecules does not coincide. In the designated conformations the basic nitrogen of the former occupies a distinct geometrical locus, and the side chain of the leucine residue has no structural correlate in the alkaloid.