Topographical requirements for δ‐selective opioid peptides

Abstract

The conformational possibilities of three different delta-selective opioid peptides, which are DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen), DCFPE (Tyr-D-Cys-Phe-D-Pen), and DRE (Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2, dermenkephalin), were explored using energy calculations. Sets of low-energy conformers were obtained for each of these peptides. The sets consisted of 61 structures for DPDPE, 32 for DCFPE, and 38 for DRE, including various types of rotamers of the Tyr and Phe side-chain groups. Comparison of the geometrical shapes of the conformers was performed for these sets using topographical considerations, i.e., examination of the mutual spatial arrangement of the N-terminal alpha-amino group, and of the Tyr and Phe side-chain groups. The results obtained suggest a model for the delta-receptor-bound conformer(s) for opioid peptides. The model suggests the placement of the Phe side chain in a definite position in space corresponding to the g- rotamer of Phe for peptides containing Phe4 and to the t rotamer for peptides containing Phe. The position of the Tyr1 side chain cannot be specified so precisely. The proposed model is in a good agreement with the results of biological testing of beta-Me-Phe4-substituted DPDPE analogues that were not considered in the process of model construction.

3D Model for TM Region of the AT-1 Receptor in Complex with Angiotensin II Independently Validated by Site-Directed Mutagenesis Data

“…The helical fragments have been assembled in a TM helical bundle following the procedure of "enhanced homology modeling," which consists of (i) determining conformations of individual helices by independent energy minimization involving all dihedral angles; (ii) superimposing the obtained conformations over the X-ray structure of Rh (18) according to sequence homology and, (iii) packing helices by finding the energetically best arrangement of the individual helices, in which dihedral angles of the backbone are "frozen" in the values obtained earlier. Accordingly, the variables for the packing procedure are the dihedral angles of the side chains for all helices, which are optimized by the algorithm developed earlier (20) as well as the 6 ϫ 7 ϭ 42 additional "global" parameters corresponding to movements of each helix as a rigid body. The packing procedure is described in detail elsewhere (21).…”

Molecular modeling and design of regioselectively addressable functionalized templates with rigidified three-dimensional structures

“…27 Subsequently, energy calculations have been performed starting from the low-energy backbone conformers found previously for the following molecules: The dihedral angle values of the Cys side chains (as well as the Nle's side chains) were optimized before final energy minimization to achieve their most favorable spatial arrangements employing the algorithm described earlier. 27 Finally, energy calculations have revealed significantly reduced conformational possibilities for the bicycles compared to the monocyclic RAFT molecules. Namely, there have been found 8 low-energy conformers (the same energy criterion) for molecule Is, 1 for molecule IIs, 4 for molecule IIIs, 3 for molecule IVs, and 14 for molecule Vs.…”

Studies of conformational isomerism in α-melanocyte stimulating hormone by design of cyclic analogues

“…First, used for opioid peptides. 20 Rigid valence geometries for the conformers of the peptide backbone for the 5-11 the Sar and Aib residues were calculated employing the fragment possessing a distance between C b 5 and C b 11 atoms SYBYL program and the values of partial atomic charges less than 7 and more than 4 Å were selected using all for these residues were calculated by the Del Re technique possible combinations of starting points described above. (SYBYL implementation).…”