Molecular Dynamics Conformation Of Opioid Peptides

工作总结：使用分子建模(分子动力学、构象搜索、蒙特卡罗)和牛视紫红质结晶结构的数据(不包括细胞内和细胞外序列)来提出增量阿片受体的模型。存在于Delta受体中的特定残基被交换到7-跨膜蛋白中。然后对各种激动剂和拮抗剂药效团进行评估，以确定最小分子模型描绘的结合口袋是否与配体匹配，并重新反映它们的已知生物活性和受体亲和力。在日本，首先通过1-H核磁共振(COSY，NOESY，HOHAHA，ROESY，DQF-COSY实验)、CD在不同的溶剂和温度条件下检测多肽的构象变化，以及结晶肽(如果有)的构象变化。芳环距离可能是Delta型拮抗剂和激动剂的一个非常重要的特征，尽管该肽具有固有的灵活性，但它们提供了“受体结合的构象”。MU激动剂在三角洲受体口袋区域表现出较差的适合性。用DMT-Tic药效团观察到的地形特征使其有别于所有其他多肽以及它与受体PIT中的侧链的相互作用。这些数据表明，多肽配体和受体的受体结合构象涉及芳环和氢键之间的堆积，Mu激动剂与那些针对Delta配体的残基相互作用很差。因此，阿片受体拮抗剂的环内距离可能预示着生物学上的差异。具有双受体结合特性或对Mu阿片受体具有选择性的多肽类似物同样有助于以预测模式使用分子建模。因此，Delta受体的模型和我们的Delta-和Mu-阿片拮抗剂和激动剂药效载体将作为设计新的有效配体的支架。

Summary of Work: Molecular modeling (molecular dynamics, conformational searching, Monte Carlo) and use of data on the crystalized structure of bovine rhodopsin (excluding the intracellular and extracellular sequences) was used to propose a model of the delta-opioid receptor. Specific residues existing in the delta receptor were exchanged in that 7-transmembrane protein. A variety of agonist and antagonist pharmacophores were then assessed to determine if the binding pocket delineated by the minimized molecular model fit the ligands and refelcted their known biological activities and receptor affinities. Conformational changes in the peptides first first examined by 1-H NMR (COSY, NOESY, HOHAHA, ROESY, DQF-COSY experiments), CD under variying solvent and temperature conditions in Japan, and crystalized peptides when available. The aromatic ring distance may be a singularly important characteristic of delta antagonists and agonists providing a "receptor-bound conformation" in spite of the inherent flexibility of the peptide. The mu agonists exhiibted a poor fit in the delta receptor pocket region. The topographical features observed with the Dmt-Tic pharmacophore differentiate it from all other peptides and its interaction with side-chains in the receptor pit. The data suggest that the presumed receptor-bound conformation of the peptide ligand and receptor involves stacking between aromatic rings and hydrogen bonding and mu agonists poorly interacted with those residues specific for delta ligands. Thus, intra-ring distance of delta-opioid antagonists may portend biological differences. Peptide analogues with dual receptor binding characteristics or selectivity for the mu opioid receptor equally assist in using molecular modeling in a predictive mode. Thus, model of the delta receptor and our delta- and mu-opioid antagonist and agonist pharmacophores will serve as scaffolds in the design of new potent ligands.