Structural Investigation of Endomorphins by Experimental and Theoretical Methods: Hunting for the Bioactive Conformation

Leitgeb, Balázs

doi:10.1002/cbdv.200790221

Cited by 32 publications

(30 citation statements)

References 51 publications

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“…Moreover, Cterminal c-and inverse c-turns were detected in the case of both cis-and trans-isomers of the stereoisomeric forms of EM2 (see Table 4). N-terminal c-turn was observed for the peptides possessing the p 2 amino acid (i.e., S [3], S [6], S [9], S [10], S [12], S [13], S [15] and S [16]) (see Figure 7A), while N-terminal inverse c-turn appeared for the molecules having the P 2 residue (i.e., S [1], S [2], S [4], S [5], S [7], S [8], S [11] and S [14]) (see Figure 7B). Taking into account the c-turns located at the C-terminal tripeptide region (see Figure 7C,D), it could be concluded that in the case of stereoisomers with the F 3 amino acid (i.e., S [1], S [2], S [3], S [5], S [6], S [8], S [10] and S [13]), the populations of inverse c-turns were larger than those of c-turns; however, in the case of stereoisomeric forms with the f 3 residue (i.e., S [4], S [7], S [9], S [11], S [12], S [14], S [15] and S [16]), the relationship between the ratios of two types of the c-turn structures was the opposite.…”

Section: Secondary Structural Elementsmentioning

confidence: 99%

“…The various structural and conformational features of EMs and their structurally modified analogs have been extensively investigated by a variety of experimental techniques and theoretical methods, so far (5). Previously, we performed the detailed conformational analysis, as well as the comprehensive structural characterization of both endomorphin-1 (EM1) and endomorphin-2 (EM2) by means of theoretical calculations (6)(7)(8)(9).…”

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confidence: 99%

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Conformational Similarities and Dissimilarities Between the Stereoisomeric Forms of Endomorphin‐2

Leitgeb¹

2011

Chem Biol Drug Des

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In this study, taking into account both the L-D and cis-trans isomerisms, a comprehensive structural characterization and a comparative conformational analysis were performed on the 32 stereoisomeric forms of opioid tetrapeptide, endomorphin-2. For all stereoisomers, the U-W and v conformational spaces were explored, in the course of which the conformational distributions, as well as the rotamer states of aromatic side chains were characterized in detail. Furthermore, the typical b-and c-turn structures, as well as the characteristic intramolecular interactions (i.e., Hbonds, aromatic-aromatic and proline-aromatic interplays) were determined. The afore-mentioned structural and conformational features identified for each stereoisomeric form were compared with one another, considering all 32 stereoisomers. The results obtained from this comparative study indicated that both similarities and dissimilarities could be observed between the stereoisomeric forms, with regard to their structural and conformational properties. This theoretical work supplied several valuable observations concerning the effects of both L-D and cis-trans isomerisms on the three-dimensional structure of parent peptide and its stereoisomers. Nevertheless, in the course of this structural investigation, it was clarified how the structural and conformational features of stereoisomeric forms differed from one another.Key words: aromatic-aromatic interaction, cis-trans isomerism, conformational analysis, endomorphin, intramolecular H-bond, L-D isomerism, proline-aromatic interaction, turn structure Endomorphins (EMs) are opioid tetrapeptides with high affinity and selectivity toward the l-opioid receptor (MOR) (1), which possess important biological effects and modulate different physiological processes (2-4). The various structural and conformational features of EMs and their structurally modified analogs have been extensively investigated by a variety of experimental techniques and theoretical methods, so far (5). Previously, we performed the detailed conformational analysis, as well as the comprehensive structural characterization of both endomorphin-1 (EM1) and endomorphin-2 (EM2) by means of theoretical calculations (6-9). Our computational studies provided new valuable results with regard to the threedimensional (3D) structure and conformational properties, as well as to the possible bioactive conformation of these tetrapeptides. However, taking into consideration all the earlier results, it is worthwhile to mention that despite the extensive research efforts focused on studying the 3D structure and bioactivity of EMs and their derivatives, a definitive model regarding the biologically active form of EM1 and EM2 is not available yet (5).It is well-known that the different types of stereoisomerism play a relevant role in the determination of peptide conformations, and they are remarkable contributors to the formation of the bioactive forms of peptides. The cis-trans isomerism of peptide bonds produces important effects on the conformational p...

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Section: Secondary Structural Elementsmentioning

confidence: 99%

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confidence: 99%

Conformational Similarities and Dissimilarities Between the Stereoisomeric Forms of Endomorphin‐2

Leitgeb¹

2011

Chem Biol Drug Des

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“…The observed efficacy for compound 16 (E max =176%) was comparable with the universal µ-receptor agonist DAMGO (E max =178% for parent compounds (higher trans ratio) were based on molecular modeling studies [81]. When the results are taken into account, a reduction of binding potency can be expected, but both analogues displayed comparable binding to endomorphins in rat brain membrane preparations [59].…”

Section: Discussionmentioning

confidence: 92%

“…In addition to this, various classic and non-canonical turn structures were identified as possible conformations of the analogues studied by the analysis of specific intramolecular H-bonds. The identified conformations provide advantageous orientation of the pharmacophore groups resulting in high-affinity binding to the µ-opioid receptor [81]. Several unique structural elements were identified as the consequence of the elongation of the peptide backbone by incorporation of a β-amino acid.…”

Section: Discussionmentioning

confidence: 99%

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Design, Synthesis and Pharmacological Evaluation of Novel Endomorphin Analogues with Multiple Structural Modifications

Mallareddy

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Free radical scavenging abilities of flavonyl‐thiazolidine‐2,4‐dione compounds

et al. 2011

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Free radical scavenging activity of flavonyl-thiazolidine-2,4-dione compounds has been evaluated using chemiluminescence, electron spin resonance spectroscopy with 5,5-dimethyl-1-pyrroline-1-oxide as spin trap and DPPH (2,2'-diphenyl-1-picrylhydrazyl) method. The examined compounds exhibited 28-50% scavenging superoxide anion radical O₂⁻ⁱ16.7-76.7% hydroxyl radical (HO•) and 9-40% DPPH radical. Compounds containing carbonyl group in their structure can be considered as antioxidants with high relevance and great biological importance.

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Structural Investigation of Endomorphins by Experimental and Theoretical Methods: Hunting for the Bioactive Conformation

Cited by 32 publications

References 51 publications

Conformational Similarities and Dissimilarities Between the Stereoisomeric Forms of Endomorphin‐2

Conformational Similarities and Dissimilarities Between the Stereoisomeric Forms of Endomorphin‐2

Design, Synthesis and Pharmacological Evaluation of Novel Endomorphin Analogues with Multiple Structural Modifications

Free radical scavenging abilities of flavonyl‐thiazolidine‐2,4‐dione compounds

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