MOLECULAR DYNAMICS CONFORMATION OF OPIOID PEPTIDES

工作总结：分子建模（分子动力学，构象 搜索，与晶体结构的叠加）被用来提出 基于受约束的和 生物活性环（Dmt-Tic）。 三维结构的特征是顺式 肽键、Tic侧链的左+方向和闭合 芳环的接近度。根据其物理化学性质 为了结合，开发了新的阿片样物质二肽拮抗剂。努力 提出d-阿片激动剂的药效团被证明是困难的， 这些七肽的灵活性。 一种方法取代了残留物 在Deltorphin中与α-氨基异丁酸（Aib）或氨基环烷烃 其在7-20个残基的肽中诱导螺旋二级结构。 分子动力学模拟表明，Aib诱导的二级结构的变化 当取代D-Ala 2或Asp 4或D-Ala 2-Phe 3，但不取代Phe时， 一个人 这为这些化合物的2-D 1H NMR分析提供了优先考虑。 用COSY，NOESY， HOHAHA、ROESY和DQF-COSY实验。 进一步的2D 1H NMR， 温度和溶剂变化将证实这些观察结果。 的 数据将用于开发D-阿片激动剂药效团， 用作进一步设计高效配体的支架。

Summary of Work: Molecular modeling (molecular dynamics, conformational searching, superimpositions with crystal structures) were used to propose a d-opioid antagonist pharmacophore based on the constrained and bioactive cyclo(Dmt-Tic). Characteristics of the 3-D structure are a cis peptide bond, gauche+ orientation of the Tic side chain and close proximity of the aromatic rings. Based on the physicochemical properties for binding, new opioid dipeptide antagonists were developed. Efforts to propose a pharmacophore for a d-opioid agonist proved difficult due to the flexibility of these heptapeptides. One approach replaced residues in deltorphin with a-aminoisobutyric acid (Aib) or aminoacycloalkanes which induce helical secondary structure in peptides of 7-20 residues. MD simulations revealed that Aib induced changes in secondary structure of deltorphin when replacing D-Ala2 or Asp4, or D-Ala2-Phe3, but not Phe alone. This provided precedence for 2-D 1H NMR analyses of these derivatives and conformational changes were observed using COSY, NOESY, HOHAHA, ROESY and DQF-COSY experiments. Further 2D 1H NMR involving temperature and solvent variation will confirm these observations. The data will be used to develop a d-opioid agonist pharmacophore which will serve as a scaffold for further design of highly potent ligands.