MOLECULAR DYNAMICS CONFORMATION OF OPIOID PEPTIDES

阿片肽的分子动力学构象

基本信息

项目摘要

Summary of Work: Molecular modeling comprised of molecular dynamics, conformational searching and superimpositions with crystal structures were used to propose a delta-opioid antagonist pharmacophore based on two sources: (1) the constrained and weakly bioactive cyclo(Dmt-Tic) and (2) the crystalline structure of N,N-dimethyl-Dmt-Tic-OH. In fact, the model of H-Dmt-Tic-OH and cyclo(Dmt-Tic) overlapped with the coordinates of the crystalline peptide with 0.6 and 03 rms, respectively; rms values under 1.0 indicate very close correlation in conformation. Characteristics of the 3-D structure are a cis peptide bond, gauche+ orientation of the Tic side chain, a near parallel orientat and close proximity of the aromatic rings. In fact, the ring distance of 5.4 angstroms appears to a common feacture of delta-opioid antagonists and differs from the more extended distances of aromatic rings (11-12 angstroms) found for delta and mu agonists. Based on the physicochemical data and further 2D 1H NMR involving temperature and solvent variation with di-, tri- and heptapeptide analogues will confirm these observations in spite of the inherent flexibility of the longer peptides. The data readily confirm the notion that peptide conformation exists in solution and is a required feature for recognition with high affinity by opioid receptor sites. New opioid di- and pentapeptide antagonists were developed based on the proposed pharmacophore for a delta-opioid agonist; for example, Dmt-D-Phe di- and pentapeptide analogues revealed that these compounds were mu-receptor antagonists. Molecualr modeling studies are continuing to delineate the differences between delta and mu antagonists and how their structure is compatible with that of the proposed receptor binding sites. Furthermore, with the availability of many more small peptide analogues with dual receptor binding characteristics or selective for the mu opioid receptor will assis in using molecular modeling in a predictive mode. The data will be used to develop delta- and mu-opioid antagonist pharmacophore which will serve as a scaffold for further design of highly potent ligands. The availability of mu-opioid antagonists would be compatible in drug treatment against cocain, heroine and morphine addiction.
工作总结:分子建模包括 分子动力学,构象搜索, 叠加与晶体结构被用来提出一个 基于两个来源的δ-阿片拮抗剂药效团:(1) 受约束的和弱生物活性的环(Dmt-Tic)和(2) N,N-二甲基-Dmt-Tic-OH的晶体结构。实际上 H-Dmt-Tic-OH和cyclo(Dmt-Tic)模型与 结晶肽的坐标为0.6和03 rms, 均方根值低于1.0表明与 构象三维结构的特征是顺式肽 键,左+Tic侧链的取向,近平行 芳环的取向和紧密接近。事实上,戒指 5.4埃的距离似乎是一个共同的特征, δ-阿片类拮抗剂,并不同于更广泛的 δ和δ的芳环距离(11-12埃) mu激动剂。基于物理化学数据和进一步的2D 1H 涉及温度和溶剂变化的NMR, 七肽类似物将证实这些观察结果, 较长肽的固有柔性。数据很容易 证实了肽构象存在于溶液中的概念, 是阿片样物质以高亲和力识别所需特征 受体位点。新的阿片样物质二肽和五肽拮抗剂, 基于δ-阿片样物质的拟议药效团开发 激动剂;例如,Dmt-D-Phe二肽和五肽类似物 表明这些化合物是μ-受体拮抗剂。 分子模拟研究正在继续描绘 δ和μ拮抗剂之间的差异以及它们如何 结构与所提出的受体结合的结构相容 网站.此外,随着更多小肽的可用性, 具有双重受体结合特征或对 μ阿片受体将阿西斯分子模拟在一个 预测模式这些数据将用于开发德尔塔-和 μ-阿片拮抗剂药效团,其将用作支架 用于进一步设计高效配体。的可用性 μ-阿片拮抗剂在药物治疗中是相容的 对抗可卡因海洛因和吗啡成瘾

项目成果

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LAWRENCE H LAZARUS其他文献

LAWRENCE H LAZARUS的其他文献

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{{ truncateString('LAWRENCE H LAZARUS', 18)}}的其他基金

MOLECULAR DYNAMICS CONFORMATION OF OPIOID PEPTIDES
阿片肽的分子动力学构象
  • 批准号:
    6290083
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Bioactivity Of Neuropeptides
神经肽的生物活性
  • 批准号:
    6838631
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Molecular Dynamics Conformation Of Opioid Peptides
阿片肽的分子动力学构象
  • 批准号:
    7007485
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Bioactivity Of Opioidmimetic Substances
阿片类物质的生物活性
  • 批准号:
    7968153
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Bioactivity Of Opioidmimetic Substances
阿片类物质的生物活性
  • 批准号:
    8149072
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
MOLECULAR BIOLOGY OF OPIOID MEMBRANE RECEPTORS
阿片类膜受体的分子生物学
  • 批准号:
    6106802
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Molecular Dynamics Conformation Of Opioid Peptides
阿片肽的分子动力学构象
  • 批准号:
    7217694
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Molecular Dynamics Conformation Of Opioid Peptides
阿片肽的分子动力学构象
  • 批准号:
    7328899
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Molecular Dynamics Conformation Of Opioid Peptides
阿片肽的分子动力学构象
  • 批准号:
    7593970
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Molecular Dynamics Conformation Of Opioid Peptides
阿片肽的分子动力学构象
  • 批准号:
    7734503
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:

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