The effect of the substitution in position 1 on the low-energy conformations of the oxytocin/vasopressin 20-membered ring was investigated by means of molecular mechanics. Three representative substitutions were considered: ([Y-mercapto-13,13-dimethyl)propionic acid (Dmp), ([3'-mercapto-13,13-cyclopentamethylene)propionic acid (Cpp), both forming strong antagonists, and (e~,c~-dimethyl-13-mercapto)propionic acid (a-Drop), forming analogs of strongly reduced biological activity, with the [3-mercaptopropionic (Mpa) residue taken as reference. Both ECEPP/2 (rigid valence geometry) and AMBER (flexible valence geometry) force fields were employed in the calculations. Three basic types of backbone conformations were taken into account which are distinguished by the type of [3-turn at residues 3 and 4: [31/13III, ]3II, and 13I'/13III', all types containing one or two intra-annular hydrogen bonds. The allowed (ring-closed) disulfide-bridge conformations were searched by an algorithm formulated in terms of scanning the disulfide-bridge torsional angle C~-S-S-C ~. The ECEPP/2 and AMBER energies of the obtained conformations were found to be in reasonable agreement. Two of the low-energy conformers of the [Mpal]-compound agreed very well with the cyclic part of the two conformers found in the crystal structure of [Mpal]-oxytocin. An analysis of the effect of [3-substitution on relative energies showed that the conformations with the N-C'-CHz-CH2 (Xl/0 and C'-CH2-CH2-S ()~) angles of the first residue around (-100 °, 60 °) and (100 °, -60 °) are not affected; this in most cases implies a left-handed disulfide bridge. In the case of c~-substitution the allowed values of ~ are close to + 60 °. This requirement, being in contradiction to the one concerning [3-substitution, could explain the very low biological activity of the c~-substituted analogs. The conformational preferences of substituted compounds can largely be explained by the analysis of local interactions within the first residue. Based on the selection of the conformations which are low in energy for both the reference and 13-substituted compounds, two distinct types of possible binding conformations were proposed, the first one being similar to the crystal conformer with a left-handed disulfide bridge, the second one having a right-handed bridge, but a geometry different from that of the crystal conformer with the right-handed bridge. The first type of disulfide-bridge
Conformationally restricted cyclic analogues of angiotensin II (ANG II), Aspl-Arg2-ValLTyr4-ValS-His6-Pro 7-Phe 8, with a link between positions 3 and 5 have considerable biological activity. It is proposed that the spatial arrangement of the pharmacophore groups of Tyr a, His 6 and Phe 8 side chains and the C-terminal carboxyl group in ANG II and active analogues is similar. Conformational analysis of ANG II and two cyclic analogues c[Sar ~, Lys3,GIuS]ANG II and c[Sarl,Hcy3,Mp:]ANG II was performed, and a geometrical comparison of the low-energy conformations of these compounds allowed one to propose a model of receptor-bound conformation in terms of the spatial arrangement of the pharmacophore groups. This model is characterised by the close spatial location of the His6-Phe 8 side chains and the Tyr 4 C-terminal carboxyl group and is stabilised by the electrostatic interaction of Arg z and the C-terminal carboxyl group.
Theoretical conformational analysis was carried out for several tetrapeptide analogues of β‐casomorphin and dermorphin containing a Phe residue in position 3. Sets of low‐energy backbone structures of the μ‐selective peptides [N‐Me‐Phe3, d‐Pro4]‐morphiceptin and Tyr‐d‐Orn‐Phe‐Asp‐NH2 were obtained. These sets of structures were compared for geometrical similarity between themselves and with the low‐energy conformations found for the δ‐selective peptide Tyr‐d‐Cys‐Phe‐d‐Pen‐OH and nonactive peptide Tyr‐Orn‐Phe‐Asp‐NH2. Two pairs of geometrically similar conformations of μ‐selective peptides, sharing no similarity with the conformations of peptides showing low affinity to the μ‐receptor, were selected as two alternative models of probable μ‐receptor‐bound backbone conformations. Both models share geometrical similarity with the low‐energy structures of the linear μ‐selective peptide Tyr‐d‐Ala‐Phe‐Phe‐NH2. Putative binding conformations of Tyr1 and Phe3 side chains are also discussed.
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