Conformational analysis of the endogenous μ-opioid agonist endomorphin-1 using NMR spectroscopy and molecular modeling

摘要: Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) is a highly selective and potent agonist of the μ-opioid receptor. To identify structural attributes unique to this opioid peptide potential sites recognition, conformational analysis has been performed using multidimensional NMR molecular modeling techniques. The spectroscopic results, derived from experiments in both DMSO water, indicate that endomorphin-1 exists cis- trans-configuration with respect Pro-omega bond approximately 25% 75% populations, respectively. In DMSO, cis-configuration adopts compact sandwich conformation which Tyr Trp aromatic rings pack against proline ring, whereas an extended conformation. Although non-random structure was not observed condensed phase dynamics calculations trans-isomers dominate population higher dielectric medium. Structural comparison trans-configurations morphine μ-peptide ligands PL-017 d-TIPP, as well δ-selective TIPP (δ-antagonist, μ-agonist) DPDPE were also suggest trans-isomer likely bioactive form. A hypothesis proposed explain μ- δ-selectivity based on presence spatially distinct selectivity pockets among these ligands.