A three‐dimensional model of the δ‐opioid pharmacophore: Comparative molecular modeling of peptide and nonpeptide ligands

A comparative molecular modeling study of δ‐opioid ligands was performed under the assumption that potent peptide and nonpeptide agonists may have common three‐dimensional (3D) arrangement of pharmacophore groups upon binding to the δ‐receptor. Low‐energy conformations of the agonists 7‐spiroindanyloxymorphone (SIOM) and 2‐methyl‐4a‐α‐(3‐hydroxyphenyl)‐1,2,3,4,4a,5,12,12a‐α‐octahydro‐quinolino[2,3,3‐ g ]isoquinoline (TAN‐67), and a partial agonist oxomorphindole (OMI) were determined by high‐temperature molecular dynamics (MD). A good spatial overlap was found for the pharmacophore groups of SIOM, TAN‐67, and OMI, including the basic nitrogen, phenol hydroxyl, and two aromatic ring. Based on this overlap we proposed a 3D pharmacophore model for nonpeptide δ‐opioid agonists with a distance of 7.0 ± 1.3 Å between the two aromatic rings and of 8.2 ± 1.0 Å between the nitrogen and phenyl ring. The potent and highly δ‐opioid receptor selective agonist [(2S,3R)‐TMT 1 ]DPDPE, which shares global backbone constraints of the 14‐membered disulfide cycle and a strong preference for the trans rotamer of the TMT 1 side chain, was chosen as a peptide template of the δ‐opioid pharmacophore. Extensive MD simulations at 300 K with the AMBER force field were performed for [(2S,3R)‐TMT 1 ]DPDPE and the less potent [(2S,3S)‐TMT 1 ]DPDPE analogue. Multiple MD trajectories were collected for each peptide starting from the x‐ray structures of DPDPE and [ L ‐Ala 3 ]DPDPE and from models proposed in the literature. Low‐energy MD conformations were filtered by the nonpeptide pharmacophore query and then directly superimposed with SIOM, OMI, and TAN‐67. Two conformers of [(2S,3R)‐TMT 1 ]DPDPE that showed the best overlap with the nonpeptide pharmacophore (rms deviation ≤ 1.0 Å for N,O atoms and centroids of two aromatic rings) were selected as possible δ‐receptor binding conformations. These conformations have similar backbone structures, and trans rotamers of the TMT 1 side‐chain group. They are reasonably close to the crystal structure of [ L ‐Ala 3 ]DPDPE, and differ significantly from the crystal structure of DPDPE. The conformer with a gauche (−) rotamer of Phe 4 is most consistent with structure–activity relationships of δ‐opioid peptides. The proposed 3D models were used for rational design of new nonpeptide δ‐receptor ligands. © 2000 John Wiley & Sons, Inc. Biopoly 53: 565–580, 2000