MOLECULAR DYNAMICS CONFORMATION OF OPIOID PEPTIDES

阿片肽的分子动力学构象

• 批准号: 6106788
• 负责人: LAWRENCE H LAZARUS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6106788
• 关键词: chemical models; computer simulation; conformation; endogenous opioid; model design /development; molecular dynamics; opioid receptor; piperazines; receptor binding

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、构象搜索和 与晶体结构的叠加被用来提出 δ-阿片拮抗剂药效团基于两个来源：(1) 受约束且生物活性较弱的环（Dmt-Tic）和（2） N,N-二甲基-Dmt-Tic-OH的晶体结构。事实上， H-Dmt-Tic-OH 和环(Dmt-Tic) 的模型与 结晶肽的坐标为 0.6 和 03 rms， 分别;均方根值低于 1.0 表明相关性非常密切 构象。 3-D结构的特征是顺式肽 键，Tic 侧链的 gauche+ 方向，接近平行 orientat并且芳香环非常接近。事实上，戒指 5.4埃的距离似乎是一个共同特征 δ-阿片拮抗剂，与更广泛的不同 发现 δ 和 的芳环距离（11-12 埃） mu激动剂。基于理化数据和进一步的2D 1H NMR 涉及温度和溶剂随着二、三和 七肽类似物将证实这些观察结果，尽管 较长肽固有的灵活性。数据一目了然 证实溶液中存在肽构象的概念 是阿片类药物高亲和力识别所需的特征 受体位点。新的阿片类二肽和五肽拮抗剂 基于 δ-阿片类药物的拟议药效团开发 激动剂；例如，Dmt-D-Phe 二肽和五肽类似物 表明这些化合物是 mu 受体拮抗剂。 分子模型研究正在继续描绘 delta 和 mu 拮抗剂之间的差异以及它们如何 结构与所提议的受体结合的结构兼容 网站。此外，随着更多小肽的出现 具有双重受体结合特性或选择性的类似物 mu阿片受体将有助于在分子模型中使用 预测模式。这些数据将用于开发三角洲和 mu-阿片拮抗剂药效团，将作为支架 用于进一步设计高效配体。的可用性 mu-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。