MOLECULAR DYNAMICS CONFORMATION OF OPIOID PEPTIDES

阿片肽的分子动力学构象

• 批准号: 6290083
• 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/6290083
• 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 and to assess the tertiary structure of the delta opioid agonist deltorphin. The study on deltorphins were conducted in order to induce structural changes in peptides in which unsual amino acids are substituted for their natural cognate, such as Aib and or aminocycloalkanes, to limit their inherent flexibility. Conformational changes were detected by 1-H NMR (using COSY, NOESY, HOHAHA, ROESY, DQF-COSY experiments) and CD under variying solvent and temperature conditions. The aromatic ring distance may be an important characteristic of delta antagonists to provide a receptor-bound conformation. The 3-D structure of H-Dmt-Tic- OH contains a cis peptide bond, gauche+ orientation of the Tic side chain, a near parallel orientation and close proximity of 5.4 A between the aromatic rings. The topographical features observed with the Dmt- Tic pharmacophore differentiate if from all other peptides. The data suggest that the presumed receptor-bound conformation involves a sandwich arrangement betweent the Dmt and Tic aromatic rings. This was confirmed by X-ray diffraction analyese on N,N(dimethyl)Dmt-Tic-OH. In fact, the small intraring distance of delta-opioid antagonists differs from the extended intramolecular distances of aromatic rings (11-12 A) found for delta, and mu antagonists as well as mu agonists. Molecular modeling continues to delineate differences between delta and mu antagonists and how their structure is compatible with proposed receptor binding sites. Small peptide analogues with dual receptor binding characteristics or selectivity for the mu opioid receptor will assist in applying molecular modeling in a predictive mode. In fact, analysis of a new opioid agonist with a weak delta antagonist activity suggests that the concept of message and address domains must be modified: the linear sequence of the peptide may not be the correct determinant to verify the amino acid residue side chains involved in these recognition sites. Thus, our delta- and mu-opioid antagonist and agonist pharmacophores will serve as scaffolds to design new potent ligands. - Molecular modeling; molecular dynamics; Monte Carlo; conformational searching; low energy conformers; petptide structure.

本文利用分子动力学、构象搜索和晶体结构叠加等分子模型，提出了一种三角洲阿片类拮抗剂药效团，并对三角洲阿片类拮抗剂三角洲海豚的三级结构进行了评估。对三角海豚的研究是为了诱导多肽的结构变化，其中不寻常的氨基酸取代了它们的天然同源物，如Aib和/或氨基环烷，以限制其固有的灵活性。利用1-H NMR（采用COSY、NOESY、HOHAHA、ROESY、DQF-COSY实验）和CD在不同溶剂和温度条件下检测构象变化。芳香环距离可能是三角洲拮抗剂提供受体结合构象的重要特征。H-Dmt-Tic- OH的三维结构包含一个顺式肽键，Tic侧链的间扭式+取向，芳香环之间的近平行取向和5.4 a的近距离。用Dmt- Tic药效团观察到的地形特征将其与所有其他肽区分开来。数据表明，假定的受体结合构象涉及Dmt和Tic芳香环之间的三明治排列。对N，N（二甲基）Dmt-Tic-OH的x射线衍射分析证实了这一点。事实上，delta-阿片拮抗剂的分子内距离较短，与delta、mu拮抗剂和mu激动剂的芳香环分子内距离较长（11-12 A）不同。分子模型继续描述delta和mu拮抗剂之间的差异，以及它们的结构如何与拟议的受体结合位点兼容。具有双受体结合特性或选择性的小肽类似物将有助于在预测模式中应用分子建模。事实上，对一种具有弱δ拮抗剂活性的新型阿片受体激动剂的分析表明，必须修改信息域和地址域的概念：肽的线性序列可能不是验证这些识别位点中涉及的氨基酸残基侧链的正确决定因素。因此，我们的-和-阿片拮抗剂和激动剂药效团将作为设计新的有效配体的支架。-分子建模；分子动力学;蒙特卡罗;构象搜索;低能构象；petptide结构。