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

Synthesis, biology, NMR and conformation studies of the topographically constrained δ‐opioid selective peptide analogs of [β‐iPrPhe3]deltorphin I

“…In a recent comparative conformational study of [TMT 1 ]DPDPE and a series of nonpeptide δ‐opioid receptor ligands (51,52), we proposed a three‐dimensional model of δ‐opioid pharmacophore, which is characterized by a distance of 7.0 ± 1.3 Å between the centers of two aromatic rings, and 8.2 ± 1.0 Å between the phenyl ring and the basic nitrogen atom. Estimates of distances between the pharmacophore groups of [(2 S ,3 R )‐β‐iPrPhe 3 ]DELT I covered during RMD simulations suggested that conformations satisfying our three‐dimensional pharmacophore model might be populated in trajectories MD1 and MD4.…”

“…First, minimized FMD structures were filtered using the above pharmacophore distance limits to narrow the number of possible candidates. A few selected peptide conformations were then superimposed with three nonpeptide compounds [SIOM (54), OMI (55) and TAN‐67 (56)], used in the development of the three‐dimensional pharmacophore model (51,52) by the best‐fit matching of four centers (basic N, hydroxyl O and centers of two aromatic rings). Three conformations of the peptide, with the four‐center RMSD from all three nonpeptide compounds of < 1.0 Å, were selected as putative bioactive conformations.…”

“…It was therefore concluded that [(2 S ,3 R )‐β‐iPrPhe 3 ]DELT I present in DMSO in an equilibrium of several types of three‐dimensional structure, and conformations that may contribute to such an equilibrium were selected. The experimental rotamer populations for the β‐iPrPhe 3 side‐chain and a previously proposed three‐dimensional model of the δ‐receptor pharmacophore (51,52), were used in an attempt to determine putative biologically active conformations of [(2 S ,3 R )‐β‐iPrPhe 3 ]DELT I. A conformation with trans rotamers of the Tyr 1 and β‐iPrPhe 3 side‐chains, which satisfied SAR data on deltorphin analogs and displayed a good fit to the three‐dimensional pharmacophore model, was selected as the most probable bioactive conformation.…”

Rational Approach to the Design of Bioactive Peptidomimetics: Recent Developments in Opioid Agonist Peptides

“…Extensive NMR, X-ray crystallography and computational chemistry studies [16][17][18] show that DPDPE retains its conformation under various conditions despite conformational flexibility at the χ angles of the side-chain groups. For this reason, constraint of side-chain moieties is used to determine the 3D pharmacophore necessary to understand the 3D requirements of a ligand's bioactivity [19] (for χ-constraint see later).…”

Design of novel peptide ligands which have opioid agonist activity and CCK antagonist activity for the treatment of pain

“…1). In previous studies in our laboratory we had developed three dimensional pharmacophore models for the delta opioid receptor (Nikiforovich et al, 1991;Collins et al, 1996;Shenderovich et al, 2000) and for the CCK-8 receptor (Nikiforovich and Hruby, 1993). Some time ago we had noted (Hruby et al, 1994) that there were some interesting topographical three dimensional similarities between the opioid receptor pharmacophore and the cholecystokinin receptor pharmacophore.…”