孤啡肽和阿片类配体与阿片孤儿受体相互作用的机制研究

摘要

AIM: To study the mechanism of interaction of nociceptin and opioids with ORL1 receptor. METHODS:Molecular dynamics study was carried out before nociceptin was manually docked into the binding site of ORL1　receptor; DOCK4.0 program was applied to dock four　stereoisomers of lofentanyl and etorphine into the binding　pocket of ORL1 receptor; Binding energies were calculated, the relationship between binding energy and binding　affinity was studied. RESULTS: Nociceptin fits well　into the binding pocket, the N-terminal FGGF tetrapeptide is located in the inner region of the binding cavity,the nociceptin (5 - 7) interacts with the conservatively　variable residues near the other end of binding pocket,and maybe determines selectivity of ORL1 receptor over dynorphin A, the positively charged core of nociceptin (8-13) binds predominantly with negatively charged EL-2 loop, which is thought to be able to mediate receptor activation. The shortest fully active analogue of nociceptin (1 - 13) is also discussed. The main difference between these two opioids and nociceptin exists in the kinds and the number of conserved and variable residues in the binding pocket and thereafter in the strength of their interaction. Prediction for binding affinities of four stereoisomers of lofentanyl has been performed based on their binding energies, the similar pharmacophore of lofentanyl and other fentanyl analogs, and the good correlation between binding energies and their experimental binding affinities ( - logKi values). CONCLUSION:Ligand docking results from this study are helpful in clarifying experimental observations of ligands interaction with opioid receptors, thus furthering biological investigations.%研究孤啡肽和阿片类配体与阿片孤儿受体相互作用的分子机制。方法：用分子动力学方法计算孤啡肽的最低能构象；通过分子对接程序将孤啡肽、阿片类配体对接到阿片孤儿受体的结合口袋中；通过结合能的计算研究配体对受体的亲和力与它们的结合能之间的关系。结果：孤啡肽(1-4)残基位于结合口袋的底部，孤啡肽(5-7)残基位于结合口袋的顶部，孤啡肽(8-17)残基与孤儿受体的第二膜外环区结合；阿片类配体和孤儿受体的结合方式与孤啡肽的情况类似，区别在于孤儿受体参与配体结合的残基种类和数量不同，因而亲和力不同；配体-受体的结合能与配体的亲和力之间有很好的相关性；预测了洛芬太尼四个异构体与阿片孤儿受体的亲和力。结论：该研究能够解释许多实验事实，有助于进一步理解阿片受体与配体相互作用的分子机制并设计新的分子生物学实验。