X-ray Structure of [D-Pen2,D-Pen5]enkephalin, a Highly Potent, .delta. Opioid Receptor-Selective Compound: Comparisons with Proposed Solution Conformations (original) (raw)
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International Journal of Peptide and Protein Research, 2009
Conformational features of a series of cyclic, penicillamine-containing enkephalin analogs, all of which display selectivity for the delta opioid receptor, were studied by 'H n.m.r. in aqueous solution. Comparison of chemical shifts, coupling constants, and temperature dependence of amide proton chemical shifts suggests different conformational features among the analogs, some of which can be related to the different primary sequences of these peptides. The observation that some of the analogs display disparate individual conformational features while exhibiting similar opioid potency and receptor selectivity suggests that such analogs may share a similar overall topography or at the least maintain the same relative orientations of key portions of the molecule.
Conformational studies of diastereomeric cyclic enkephalins by1H-NMR and computer simulations
Biopolymers, 1987
We report the solid-phase synthesis and conformational analysis of a 14-membered, cyclic enkephalin analog, H-Tyr-~$-~-A,bu-Gly-Phe-~-Leu-] (where A,bu represents a,ydiaminobutyric acid). The results from the guinea pig ileum (GPI) and mouse vas deferens (MVD) assays show that the analog, though active, has little seledivity for the p or 8 opioid receptors. Conformational analysis is carried out using 'H-nmr and computer simulations, including molecular dynamics and energy minimizations. The results obtained here are compared with the findings of our studies carried out on the p-receptor-selective diastereomer, Chem. SOC. 101,400&4013]. This comparison allows for insight into the regiospecificity of these cyclic enkephalin analogs. H-Tyr-~[-D-A,b~-Gly-Phe-Leu-] [N. M d , M. H m , and M. Goodman (1985) J. Am.
The conformation of enkephalin bound to its receptor: an “elusive goal†becoming reality
Frontiers in Molecular Biosciences, 2014
The availability of solid state structures of opioid receptors has prompted us to reconsider a crucial question concerning bioactive peptides: can their conformation be studied without any knowledge of the structure of their receptors? The possibility of giving a meaningful answer to this query rests ultimately on the ease of dealing with the flexibility of bioactive peptides, and amongst them one of the most flexible bioactive peptides, enkephalin. All solution studies of enkephalin hint at an inextricable mixture of quasi isoenergetic conformers. In this study we refer to the only NMR work that yielded inter-residue NOEs, performed at very low temperature. In the present work, we have used the simplest possible docking methods to check the consistency of the main conformers of enkephalin with the steric requirements of the active site of the receptor, as provided by the crystal structure of its complex with naltrindole, a rigid antagonist. We show that the conformers found in the equilibrium mixture at low temperature are indeed compatible with a good fit to the receptor active site. The possible uncertainties linked to the different behavior of agonists and antagonists do not diminish the relevance of the finding.
Biopolymers, 1991
In order to study structure-activity relationships of enkephalin-related analogues, we report the biological activity and conformational analysis of four 14-membered cyclic enkephalin analogues with P-(1-naphthy1)alanine in place of phenylalanine a t the fourth position, Tyr-c [ D-A,bu-Gly-(L and D)-PNal(1)-(L and D)-Leu]. The L-PNal(1)-containing analogues display higher activity at both the p and 6 receptors than the corresponding analogues with the L-Phe residue. In contrast to the linear enkephalins, the cyclic analogues with the D-PNal(1) residue are also active at the p receptor since the relative spatial arrangement of functional groups required for biological activity is achieved by the constrained nature of the cyclic molecules. A comparison of the findings from the conformational analysis and biological assays establishes that relatively extended structures, in which the two aromatic side chains are oriented in opposite directions with a-14 8, separation, is required for activity at the p receptor. On the other hand, folded conformations with nearly parallel orientations and a close proximity (< lOA) of the aromatic rings of the Tyr and pNal(1) residues are required for activity at the 6 receptor. It should be noted that the overall structures and thus the biological profiles of the 14-membered cyclic enkephalin analogues are strongly dependent on the conformation of the second residue. The folded conformations with parallel orientation of the two aromatic side chains of Tyr-c [ D-A,bu-Gly-L-PNal(1)-D-Leu] is stabilized by an interaction between the Tyr phenolic OH proton and @Nal(1) C*O groups. This analogue, which shows the highest activity at both the p and 6 receptors among the four stereoisomers studied, displays an increase of the fraction of the side-chain XI = t conformer for the PNal(1) residue. It is concluded that the incorporation of the D-Leu residue at the fifth position increases the relative fraction of the folded conformations with parallel orientation of the aromatic side chains, and hence enhances activity at the 6 receptor as compared to the corresponding L-Leu containing analogue.
Topographically designed analogs of [cyclic] [D-Pen2,D-Pen5]enkephalin
Journal of Medicinal Chemistry, 1991
The conformationally restricted, cyclic disulfide-containing 6 opioid receptor selective enkephalin analogue [D-Penz,~-Pens]enkephalin (1, DPDPE) was systematically modified topographically by addition of a methyl group at either the p r o 4 or pro-R position of the fi carbon of an ~-Phe' or ~P h e ' reeidue to give [(2S,3S)-fl-MePhe4]DPDPE (2), [(2R,3R)-8-MePhe4]DPDPE (3), [(2S,3R)-8-MePhe4]DPDPE (4), and [(2R,3S)-B-MePhe4]DPDPE (5).
Conformational preferences of a few enkephalin unsaturated analogs
Journal of Molecular Structure, 1994
The conformationalbehaviorof enkephalinanalogscontaining0'-(3 unsaturatedresidueswas studiedemploying a recentmodification (G. Alagona,C. Ghio and C. Pratesi,J. Comput.Chem.,12 (1991) 934)of an existing force field for nucleicacidsandproteins(S., J. Am. Chern.Soc., 106 (1984) 765) with molecularmechanicsand moleculardynamicssimulations. On the basis of the structuresobtained,the rationaleproposedfor the morphine-likeactivity of enkephalins(i.e. the presenceof j-i-turn of type II', consideredimportantfor the binding to opiatereceptors)was checkedandconfirmedon the basis of topological features associatedwith a compact positioning of the aromatic side chains, tyrosine and phenylalanineor dehydrophenylalanine. The molecularelectrostaticpotential in the plane perpendicularto the a -i double bond may account only in part for the enhancedpotency often observedin unsaturatedcompounds.and attributedto the intrinsic reactivity of the doublebond toward nucleophilicsites onthe opiatereceptoror to a stronger binding to receptors.In the presence of the solvent,describedas acontinuousdielectricmedium,mostof the leaststable conformationsin vacuo are greatly stabilized,thus becomingevenmore favored than the gas-phase minimum-energy structures.Interestinglyenough,the solventstabilizationis noticeablenot only for theextendedconformers,as expected. but also for several.a-turn structuresof type II'.
International Journal of Peptide and Protein Research, 2009
Conformational analyses of the cyclic opioids H-Tyr-D-Pen-Gly-Phe-D-Pen-OH (DPDPE) and H-Tyr-D-Cys-Gly-Phe-D-Cys-OH (DCDCE) have been performed using the AMBER program. DPDPE is considerably more selective for delta-receptors than DCDCE. Using the RNGCFM program, a large number of ways were found to close the 14-membered disulfide-containing ring structure. However, intramolecular hydrogen bonds were only possible in gamma-turn and inverse gamma-turn conformations centered on the glycine residue which were associated with opposite chiralities of the disulfide bond. With the cyclic part of the molecules in either a gamma-turn or inverse gamma-turn, a systematic conformational analysis was performed on the tyrosine and phenylalanine sidechains. This showed that conformers with the tyrosine and phenylalanine phenyl rings in the vicinity of the disulfide bond were preferred due to attractive van der Waals forces. For DPDPE, however, this was only possible with a positive dihedral angle for the disulfide bond due to the presence of the beta-carbon methyls of Pen'. In contrast, these preferred conformers were possible with both chiralities of the disulfide bond in DCDCE. Conformational entropies and free energies were computed from the translational, rotational, and vibrational energy levels available to each conformer. The conformational entropies were found to vary significantly and to result in a reordering of the lowest energy minima. Based on these conformational differences in DPDPE and DCDCE and their differing pharmacological selectivities, tentative conformational preferences for delta-and mu-receptor opioid peptides are proposed.
International journal of peptide and protein research, 1989
Conformational analysis of the cyclic opioids H-Tyr-D-Pen-Gly-Phe-D-Pen-OH (DPDPE) and H-Tyr-D-Cys-Gly-Phe-D-Cys-OH (DCDCE) have been performed using the AMBER program. DPDPE is considerably more selective for delta-receptors than DCDCE. Using the RNGCFM program, a large number of ways were found to close the 14-membered disulfide-containing ring structure. However, intramolecular hydrogen bonds were only possible in gamma-turn and inverse gamma-turn conformations centered on the glycine residue which were associated with opposite chiralities of the disulfide bond. With the cyclic part of the molecules in either a gamma-turn or inverse gamma-turn, a systematic conformational analysis was performed on the tyrosine and phenylalanine sidechains. This showed that conformers with the tyrosine and phenylalanine phenyl rings in the vicinity of the disulfide bond were preferred due to attractive van der Waals forces. For DPDPE, however, this was only possible with a positive dihedral angle ...
Journal of Peptide Science, 2001
Six novel cyclic enkephalin analogues have been synthesized. Cyclization of the linear peptides containing basic amino acid residues in position 2 and 5 was achieved by treatment with bis(4-nitrophenyl)carbonate. It was found that some of the compounds exibit unusually high µ-opioid activity in the guinea pig ileum (GPI) assay. The 18-membered analogue cyclo(Nε,Nβ′-carbonyl--Lys2,Dap5)enkephalinamide turned out to be one of the most potent µ-agonists reported so far. NMR spectra of the peptides were recorded and structural parameters were determined. The conformational space was exhaustively examined for each of them using the electrostatically driven Monte Carlo method. Each peptide was finally described as an ensemble of conformations. A model of the bioactive conformation of this class of opioid peptides was proposed. Copyright © 2001 European Peptide Society and John Wiley & Sons, Ltd.
Conformational sampling of bioactive conformers: a low-temperature NMR study of15N-Leu–enkephalin
Journal of Peptide Science, 1998
Conformational studies of enkephalins are hampered by their high flexibility which leads to mixtures of quasi-isoenergetic conformers in solution and makes NOEs very difficult to detect in NMR spectra. In order to improve the quality of the NMR data, Leu -enkephalin was synthesized with 15 N-labelled uniformly on all amide nitrogens and examined in a viscous solvent medium at low temperature. HMQC NOESY spectra of the labelled Leu-enkephalin in a DMSO d6 /H 2 O) mixture at 275 K do show numerous NOEs, but these are not consistent with a single conformer and are only sufficient to describe the conformational state as a mixture of several conformers. Here a different approach to the structure -activity relationships of enkephalins is presented: it is possible to analyse the NMR data in terms of limiting canonical structures (i.e. iand k-turns) and finally to select only those consistent with the requirements of l selective agonists and antagonists. This strategy results in the prediction of a family of conformers that may be useful in the design of new l selective opioid peptides.