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.

工作摘要：由分子动力学，构象搜索和与晶体结构的叠加组成的分子建模用于提出三角洲阿片类拮抗剂药理，并评估三角洲阿片类激动剂的第三级结构。进行了关于三翼丁物的研究是为了诱导肽的结构变化，在该肽中，不纯种氨基酸被取代其自然同源，例如AIB和氨基散虫，以限制其固有的柔韧性。通过1-H NMR（使用舒适，Noesy，Hohaha，Roesy，DQF-Cosy实验）检测到构象变化，在变化溶剂和温度条件下CD检测到CD。芳族环距离可能是提供受体结合构象的三角洲拮抗剂的重要特征。 H-DMT-TIC-OH的3-D结构包含一个顺式肽键，TIC侧链的Gauche+方向，几乎平行的方向以及在芳族环之间的5.4 a的接近度。如果与所有其他肽，则使用DMT-PharmaCochore观察到的地形特征会区分。数据表明，假定受体结合的构象涉及DMT和TIC芳香环的三明治布置。 N，N（二甲基）DMT-TIC-OH上通过X射线衍射分析蛋白证实了这一点。实际上，三角洲阿片类拮抗剂的较小的内部内部距离与芳族环（11-12 a）的延长分子内距离（11-12 A）不同，MU拮抗剂以及MU激动剂。分子模型继续描绘了三角洲和MU拮抗剂之间的差异，以及它们的结构如何与所提出的受体结合位点兼容。具有双重受体结合特性或对MU阿片受体的选择性的小肽类似物将有助于在预测模式下应用分子建模。实际上，对具有较弱的三角洲拮抗剂活性的新阿片类激动剂的分析表明，必须修改消息和地址域的概念：肽的线性序列可能不是验证这些识别位点涉及的氨基酸残基侧链的正确决定因素。因此，我们的三角洲和阿片类药物拮抗剂和激动剂药物团将用作设计新的有效配体的脚手架。 - 分子建模；分子动力学；蒙特卡洛；构象搜索；低能量构象体；佩蒂德结构。