Molecular dynamics conformations of deltorphin analogues advocate delta opioid binding site models
Bryant, S.D.; Attila, M.; Salvadori, S.; Guerrini, R.; Lazarus, L.H.
Peptide Research 7(4): 175-184
1994
ISSN/ISBN: 1040-5704 PMID: 7696838 Document Number: 435213
Multi-site binding models for the delta opioid receptor were studied in vitro with (3H)DPDPE as the labeled ligand using analogues of deltorphin C (H-Tyr-D-Ala- Phe-Asp-Val-Val-Gly-NH-2) altered at position 4. Modifications included a change in chirality (L- to D-Asp-4), increased length of the anionic side-chain (Glu-4), elimination of the charged group (Abu-4), addition of an anionic group (Gla-4), and change in backbone conformation (Pro-4). All of the peptides had relatively high 8 affinities (0.09 to 1.15 nM); the major variability in delta selectivity resided in changes in mu affinities (1.6 to 530 nM). Three analogues (Glu-4 D-ASp-4 and Pro-4) revealed better fits to two-site binding models (Hill coefficients lt 0.850 with narrow 95% confidence intervals and P lt 0.0001). Deltorphin C and analogues containing Gla-4 and Abu-4 (which were weakly delta selective), as well as deltorphin A (H-Tyr-D-Met-Phe-His-Leu-Met-Asp-NH-2), fitted one-site binding models. Molecular dynamics simulations performed on deltorphin C and Abu-4 exhibited similarities in the tertiary structure of their low energy conformers, while differing from the three-dimensional structures of the analogues containing Glu-4, D-Asp-4 and Pro-4 substitutions. The data provide support that the three-dimensional architecture of an opioid peptide is an important factor in the designation of delta opioid receptor subtypes.