Conformational search in enkephalin analogues containing a disulfide bond.

A systematic conformational search has been performed for the 14-membered ring in model compounds for disulfide-containing enkephalin analogues. The model compounds examined are [formula: see text], and the corresponding compounds with L-amino acids at the C-terminus. About 100 starting conformations were generated for each compound with the RNGCFM program and energy minimized with the AMBER program. Between 21 and 38 conformers within 3 kcal/mole of the apparent global minimum were found for each compound. There appeared to be fewer possible conformations of the disulfide-containing side chain than of the main chain. [formula: see text], whose parent compound is selective for opioid delta receptors, was found to prefer conformers with a positive dihedral angle of the disulfide bond, which is consistent with the previous proposal that delta-receptor selectivity may be associated with this conformational preference. Additional calculations were performed on the complete structure of [formula: see text] (DPDPE) with various possible conformations of the tyrosine and phenylalanine side chains. Conformational free energies and entropies were computed for these conformers from the molecular vibrations obtained from a normal mode analysis. As was found previously, conformers with low energies tended to have lower entropies, which resulted in a narrowing of the free energy differences between conformers. A conformer is identified that has the lowest energy hitherto found for DPDPE. It is suggested that DPDPE may be a useful compound for evaluating conformational search strategies because of its relatively small size and the number of conformers that have already been identified. Conformational energy calculations are also reported for naltrindole using the MM2(87) program. Naltrindole, which incorporates two aromatic 6-membered rings in a rigid structure, is a highly selective and potent opioid delta-receptor antagonist and may be an important clue regarding the biologically active conformer of DPDPE. Various conformers of DPDPE have been superimposed quantitatively onto the structure of naltrindole using the SUPER program and those conformers of DPDPE that are the best fit to naltrindole are reported.