MOLECULAR DYNAMICS CONFORMATION OF OPIOID PEPTIDES

工作总结：利用分子动力学、构象搜索和晶体结构叠加的分子模拟方法，提出了一个三角洲阿片拮抗剂药效团，并评估了三角洲阿片激动剂Deltorphin的三级结构。对Deltorphins的研究是为了诱导多肽的结构变化，其中不合适的氨基酸取代了它们的天然同源物，如AIB和/或氨基环烷烃，以限制其固有的灵活性。用1-H核磁共振(COSY、NOESY、HOHAHA、ROESY、DQF-COSY实验)和CD检测了不同溶剂和温度条件下的构象变化。芳环距离可能是Delta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多肽键，Tic侧链的Guche+取向，芳环之间的近平行取向和5.4A的紧密接近。用DMT-Tic药效团观察到的地形特征与所有其他多肽不同。这些数据表明，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。N，N(二甲基二甲基)DMT-Tic-OH的X射线衍射分析证实了这一点。事实上，Delta-阿片类拮抗剂的小侵入距离不同于Delta、Mu拮抗剂和Mu激动剂的芳环分子内延伸距离(11-12A)。分子模拟继续描绘Delta和Mu拮抗剂之间的差异，以及它们的结构如何与建议的受体结合位点相兼容。具有双受体结合特性或对Mu阿片受体具有选择性的小肽类似物将有助于以预测模式应用分子建模。事实上，对一种具有弱Delta拮抗剂活性的新阿片激动剂的分析表明，信息域和地址域的概念必须修改：多肽的线性序列可能不是验证这些识别位点所涉及的氨基酸残基侧链的正确决定因素。因此，我们的Delta-和Mu-阿片类拮抗剂和激动剂药效团将作为支架来设计新的有效配体。-分子模拟；分子动力学；蒙特卡罗；构象搜索；低能构象；球状结构。

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.