In the present work, a series of simulation tools were used to determine structure-activity relationships for the endomorphins (EMs) and derive μ-pharmacophore models for these peptides. Potential lowest energy conformations were determined in vacuo by systematically varying the torsional angles of the Tyr 1-Pro 2 (ω 1) and Pro 2- Trp 3/Phe 3 (ω 2) as tuning parameters in AM1 calculations. These initial models were then exposed to aqueous conditions via molecular dynamics simulations. In aqueous solution, the simulations suggest that endomorphin conformers strongly favor the trans/trans pair of the ω 1/ω 2 amide bonds. From two-dimensional probability distributions of the ring-to-ring distances with respect to the pharmacophoric angles for EMs, a selectivity range of μ 1 is ca. 8.3~10.5 Å for endomorphin-2 and selectivity range of μ 2 is ca. 10.5~13.0 Å for endomorphin-1 were determined. Four-component μ-pharmacophore models are proposed for EMs and are compared to the previously published δ- and κ-pharmacophore models.
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