Structure-activity relationships of alphaS1-casomorphin using AM1 calculations and molecular dynamics simulations.

This paper investigates the structure-activity relationships of alphaS1-casomorphin (alphaS1-CM) using AM1 calculations and molecular dynamics (MD) simulations. Previous studies have shown that this peptide has remarkable opioid actions, and not only has a high affinity toward all three subtypes (kappa1-kappa3) of the kappa-opioid sites, but also inhibits the proliferation of the T47D human breast cancer cell line. The systematic conformer search performed by the AM1 calculations is based on the torsional angles of the Val2-Pro3 (omega2) and Phe4-Pro5 (omega4) amide bonds. The AM1 results reveal that the alphaS1-CM conformers strongly favor the cis/cis pair of the omega2/omega4 amide bonds in the minimized energy state. Furthermore, the picture of these stable conformers is found to be a strong interaction of the coulomb's force between two terminuses. MD simulations are performed to investigate the features of both the structural stability and pharmacological activity of alphaS1-CM in aqueous solution. The simulation results reveal that the omega2/omega4 amide bonds favor the cis/cis status in the stable state. Furthermore, the pharmacophoric distance between two aromatic rings is found to be 5.0 approximately 5.4A. The chi1 rotamers of the Tyr and Phe residues show a preference for gauche (-) and trans, respectively. The side chain rotamers of alphaS1-CM are competed to those of other opioid ligands with a known potency and selectivity for delta- and mu-opioid receptors. Finally, we address a likely kappa pharmacophore model compared to the delta pharmacophore model.