X‐ray studies on ligands

Deschamps, Jeffrey R.; Flippen‐Anderson, Judith L.; George, Clifford

doi:10.1002/bip.10308

Cited by 9 publications

(11 citation statements)

References 28 publications

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“…X-ray crystallography of constrained peptides and calculations clearly show this [1,2]. The torsional angles in the rotamers reported in Figure 2 are the different values of the χ 1 torsion angle.…”

Section: Introductionmentioning

confidence: 94%

Conformationally Constrained Histidines in the Design of Peptidomimetics: Strategies for the χ-Space Control

Stefanucci

Pinnen

Feliciani

et al. 2011

IJMS

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A successful design of peptidomimetics must come to terms with χ-space control. The incorporation of χ-space constrained amino acids into bioactive peptides renders the χ1 and χ2 torsional angles of pharmacophore amino acids critical for activity and selectivity as with other relevant structural features of the template. This review describes histidine analogues characterized by replacement of native α and/or β-hydrogen atoms with alkyl substituents as well as analogues with α, β-didehydro unsaturation or Cα-Cβ cyclopropane insertion (ACC derivatives). Attention is also dedicated to the relevant field of β-aminoacid chemistry by describing the synthesis of β2- and β3-models (β-hHis). Structural modifications leading to cyclic imino derivatives such as spinacine, aza-histidine and analogues with shortening or elongation of the native side chain (nor-histidine and homo-histidine, respectively) are also described. Examples of the use of the described analogues to replace native histidine in bioactive peptides are also given.

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Section: Introductionmentioning

confidence: 94%

Conformationally Constrained Histidines in the Design of Peptidomimetics: Strategies for the χ-Space Control

Stefanucci

Pinnen

Feliciani

et al. 2011

IJMS

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“…Computational studies of enkephalin structure support this hypothesis 12. The δ-opioid receptor may be sensitive to a wide range of conformations with aromatic separations of 5 to 15 Å 12,20. Leucine enkephalin (YGGFL), which demonstrates δ-receptor activity, appears to form structures with a wide range of aromatic sidechain separations 12…”

Section: Introductionmentioning

confidence: 95%

“…In hydrophobic or membrane environments enkephalins appear to adopt more compact and structured configurations due to interaction with the lipid bilayer 5,6,14-19. The average distance between the pharmacore groups (Tyr and Phe) may correlate with selectivity toward different opioid receptors 20. Computational studies of enkephalin structure support this hypothesis 12.…”

Section: Introductionmentioning

confidence: 96%

Conformational Heterogeneity of a Leucine Enkephalin Analogue in Aqueous Solution and Sodium Dodecyl Sulfate Micelles: Comparison of Time-Resolved FRET and Molecular Dynamics Simulations

2009

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We have undertaken time-resolved Förster resonance energy transfer (FRET) and molecular dynamics simulations to analyze conformations and conformational heterogeneity of an analog of leucine enkephalin in solution and in the presence of SDS micelles. Enkephalins are opioid pentapeptides that interact with opioid receptors in the central nervous system. We used time-correlated single-photon counting to detect energy transfer between the N-terminal tyrosine and a tryptophan residue substituted for phenylalanine at the 4 position. FRET from Tyr to Trp was measured over a temperature range from 5°C to 55°C in aqueous solution. By taking into account Tyr rotamer interconversion rates measured previously, we determined average distances between Tyr and Trp for the two populated rotameric conformations of Tyr. Molecular dynamics simulations (100 ns) support this analysis and indicate extensive conformational heterogeneity. The simulations also predict that the FRET orientational factor is correlated with the Tyr-Trp separation. Failure to account for the correlation between orientation and distance results in errors that appear to be largely offset in YGGWL by a weighting bias inherent in the R−6 dependence of the energy-transfer rate. The Tyr lifetimes decrease upon titration of the peptides with SDS, indicating formation of compact conformations of the peptide in the micelle environment. This result is consistent with the conjecture that the lipid environment may induce formation of bioactive conformations of the peptide.

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“…10, and the relation of such measures to activity is hinted at in Ref. 11.) It has often been suggested that the structural conformation of enkephalin's backbone might play an essential role in determining whether a particular population of enkephalin molecules will be more or less predisposed to binding to a given opiate receptor subtype.…”

Section: Introductionmentioning

confidence: 99%

The probability distribution of side‐chain conformations in [Leu] and [Met]enkephalin determines the potency and selectivity to μ and δ opiate receptors

2003

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The structure of enkephalin, a small neuropeptide with five amino acids, has been simulated on computers using molecular dynamics. Such simulations exhibit a few stable conformations, which also have been identified experimentally. The simulations provide the possibility to perform cluster analysis in the space defined by potentially pharmacophoric measures such as dihedral angles, side-chain orientation, etc. By analyzing the statistics of the resulting clusters, the probability distribution of the side-chain conformations may be determined. These probabilities allow us to predict the selectivity of [Leu]enkephalin and [Met]enkephalin to the known mu- and delta-type opiate receptors to which they bind as agonists. Other plausible consequences of these probability distributions are discussed in relation to the way in which they may influence the dynamics of the synapse.

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X‐ray studies on ligands

Cited by 9 publications

References 28 publications

Conformationally Constrained Histidines in the Design of Peptidomimetics: Strategies for the χ-Space Control

Conformationally Constrained Histidines in the Design of Peptidomimetics: Strategies for the χ-Space Control

Conformational Heterogeneity of a Leucine Enkephalin Analogue in Aqueous Solution and Sodium Dodecyl Sulfate Micelles: Comparison of Time-Resolved FRET and Molecular Dynamics Simulations

The probability distribution of side‐chain conformations in [Leu] and [Met]enkephalin determines the potency and selectivity to μ and δ opiate receptors

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