MOLECULAR DYNAMICS CONFORMATION OF OPIOID PEPTIDES

利用分子动力学构象的计算机模拟应用 阿片肽的分析。多肽构象的可视化 中的二面体的变化进行推断。 具有以下组成残基的主链、手性和侧链 对阿片类药物结合倾向的直接影响。获得的知识 了解这些相互作用的机制对于 用激动剂或拮抗剂设计新型多肽的合理途径 活动。计算机模拟使用了各种分子动力学程序， 例如MacroModel、Spartan、Amber、MULTI和BioSym Silicon Graphics Indigo2。阿片类二肽的分子构象 揭示了最低能量构象的簇表现出 DMT和Tic芳环之间的平行度。一个可比的 观察到了最低能量团簇的结构 二酮基哌嗪，环(DMT-Tic)，代表一类新的阿片类药物 没有带电官能团的多肽与之特异相互作用 D受体。然而，由于这种构象类似于 受体亲和力较高的化合物c(Tyr-Tic)的晶体结构 3.5个数量级的边框，这表明即使化合物可能 达到类似的低能态，这并不意味着相似 在生物活性构象中。这些数据提出了三个观点 关于以下各项所需最低要求的附件假设 阿片类拮抗剂与受体的结合：(I)疏水性p-p 多肽与受体残基的相互作用；(Ii)相互间的氢键 受体中的酪胺羟基和电荷残基；和(Iii)阳离子-p 涉及受体阳离子和配体芳香环的相互作用。

Computer modeling applications utilized molecular dynamics conformational analyses of opioid peptides. Visualization of peptide conformation permits inferences to be drawn on changes in the dihedrals in the backbone, chirality and side-chain of the constituent residues that have direct impact on the binding proclivities of opioids. Knowledge gained from understanding the mechanisms of these interactions are essential for a rational approach to designing new peptides with agonist or antagonist activity. Computer modeling used various molecular dynamics programs, such as MacroModel, Spartan, AMBER, MULTI, and BioSym operating on a Silicon Graphics Indigo2. Molecular conformation on the opioid dipeptide revealed that the cluster of lowest energy conformers exhibited parallelism between the aromatic rings of Dmt and Tic. A comparable structure was observed for the lowest energy cluster of a diketopiperazine, cyclo(Dmt-Tic), which represents a new class of opioid peptides without a charged functionality that interact specifically with the d receptor. However, since this conformation was analogous to the crystal structure of c(Tyr-Tic), a compound whose receptor affinity is 3.5 borders of magnitude less, suggests that even though compounds may attain comparable low energy states, that does not indicate a similarity in the bioactive conformations. These data proposed a three-point attachment hypotheses as for the minimum requirements necessary for binding an opioid antagonist to a receptor: (i) hydrophobic p-p interactions between peptide and receptor residues; (ii) H-bond between tyramine OH and charge residue in receptor; and (iii) cation-p interactions involving a receptor cation and aromatic rings of ligand.