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.

工作摘要：分子建模包括 分子动力学，构象搜索和 使用晶体结构的叠加来提出 基于两个来源的三角洲阿片类拮抗剂药效团：（1） 受约束和弱生物活性环（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）的模型与 与0.6和03 rms的晶肽的坐标， 分别; 1.0以下的RMS值表示非常紧密的相关性 构象。 3-D结构的特征是顺式肽 键，gauche+ tic侧链的方向，几乎平行 东方和芳香环的近距离。实际上，戒指 5.4埃的距离似乎是一个常见的 三角洲阿片类拮抗剂，与更扩展的拮抗剂不同 Delta和 MU激动剂。基于理化数据和进一步的2d 1h NMR涉及温度和溶剂变化，二，三和溶剂 尽管 较长肽的固有灵活性。数据很容易 确认溶液中存在肽构象的观念 是阿片类药物高亲和力识别的必需功能 受体位点。新的阿片类二肽和五肽拮抗剂是 基于提议的三角洲阿片类药物的拟议的药效团开发 激动剂；例如，DMT-D-PHE DI-和五肽类似物 表明这些化合物是MU受体拮抗剂。 分子建模研究正在继续描绘 三角洲和MU拮抗剂之间的差异以及他们如何 结构与所提出的受体结合的结构兼容 站点。此外，还有更多小肽的可用性 具有双重受体结合特征或选择性的类似物 MU阿片受体将在A中使用分子建模 预测模式。数据将用于开发delta-和 Mu-Apoid拮抗剂药片学团将作为脚手架 用于进一步设计高度有效的配体。可用性 Mu-Apoid拮抗剂在药物治疗中兼容 反对可卡因，女主角和吗啡成瘾。