Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, 62 Temesvári körút, Szeged H-6720, Hungary.
J Mol Graph Model. 2010 Feb 26;28(6):495-505. doi: 10.1016/j.jmgm.2009.11.006. Epub 2009 Dec 3.
Structural determinants of binding to the mu-opioid receptor, an important target in analgesia, attract great scientific attention. Many natural and synthetic peptides and peptidomimetics were shown previously to bind to this receptor selectively but there is no consensus about the structure responsible for biological activity. No high resolution structure of this receptor is available and the binding site of ligands is not exactly known. However, mu-opioid ligands with similar affinity and selectivity should possess at least one common structural feature. Comparative structural analysis of such ligands, considering adequate representation of binding conditions, may reveal key features of bioactivity. In this study ten mu-opioid receptor ligands, DAMGO, Tyr-W-MIF-1, morphiceptin, endomorphin-1 and 2 and their analogues, possessing different affinity and selectivity, were examined using molecular dynamics. Conformational preference of these molecules was determined in H(2)O and DMSO along with structural properties previously proposed to be important for binding. Four of such structural requirements were confirmed to be important, providing a possible structural model of receptor binding. Simultaneous fulfillment of these requirements results most likely in high affinity binding to the mu-opioid receptor.
与μ-阿片受体结合的结构决定因素，是镇痛的一个重要靶点，引起了极大的科学关注。先前已经表明，许多天然和合成肽和肽模拟物可以选择性地与该受体结合，但对于负责生物活性的结构尚无共识。该受体没有高分辨率结构，配体的结合位点也不完全清楚。然而，具有相似亲和力和选择性的μ-阿片受体配体应该至少具有一个共同的结构特征。考虑到结合条件的充分代表性，对这些配体进行比较结构分析，可以揭示生物活性的关键特征。在这项研究中，使用分子动力学研究了十个μ-阿片受体配体，包括 DAMGO、Tyr-W-MIF-1、吗啡肽、内吗啡肽-1 和 2 及其类似物，它们具有不同的亲和力和选择性。在 H(2)O 和 DMSO 中确定了这些分子的构象偏好，以及以前被认为对结合很重要的结构特性。确认了其中四个结构要求很重要，为受体结合提供了一个可能的结构模型。这些要求的同时满足很可能导致与μ-阿片受体的高亲和力结合。
