Molecular modeling on solvent effect and interaction mechanism of fentanyl analogs to μ-opioid receptor^1  

芬太尼类似物溶剂化效应和与μ阿片受体作用机制的分子模拟(英文)

作　　者：黄小琴[1] 蒋华良[1] 罗小民[1] 戎锁宝 顾建德 谭小健 朱友成 陈凯先 嵇汝运[1] 曹阳[2] 

机构地区：[1]中国科学院上海药物研究所 [2]苏州大学化学系

出　　处：《Acta Pharmacologica Sinica》2000年第1期48-56,共9页中国药理学报（英文版）

基　　金：Project supported by the Key Programs of National Natural Science Foundation of China (No 29790123 and 29725203).

摘　　要：AIM: To do theoretical study about solvation effect and interaction mechanism of fentanyl analogs (FA) to μ opioid receptor (μOR). METHODS: Flexible docking (FlexiDock) was performed by using the possible active conformations of FA and optimized 3D structure of μ opioid receptor. Binding energies were calculated. Comparative molecular force field analysis (CoMFA) and quantitative structure activity relationship (QSAR) studies were carried out based on results of flexible docking. Solvation effects were considered by studying interaction of FA with water molecules. Partial least square (PLS) analysis was used to calculate regression equation for analgesic activities using binding energies as descriptive factor. RESULTS: 1) Binding conformations of these analogs derived by flexible docking were reasonable. 2) It was most possible for the FA to exist in water solution in the form of binding conformations. 3) Energetic calculation and QSAR analysis showed a good correlation between the calculated binding energies of FA and their analgesic activities. 4) Based on the 3D-model, the possible interaction mechanism of FA with uuuuu opioid receptor can be illustrated reasonably. CONCLUSION: The nature of the correlation between the binding affinities and analgesic activities of FA was explained by our modeling result.目的:研究芬太尼类配体(FA)的溶剂化效应以及和μ阿片受体的相互作用机制。方法:将芬太尼类配体进行溶剂化,柔性对接到μOR的七个α螺旋束之内,计算结合能并进行CoMFA和QSAR研究。结果:(1)得到FA的溶剂化模型。(2)得到FA与μOR相互作用的模型,FA通过静电作用、氢键和疏水作用与μOR结合。(3)描述了μOR中适合于FA的结合口袋,主要位于μOR的第3,4,5,6,7跨膜螺旋中,形成口袋的主要残基为Ile144,Asp147,Tyr148,Met151,Trp192,Leu200,Ile238,Ile242,His297,Val300,Tyr326,Ser329。(4)FA-μOR的结合能与FA的镇痛活性之间有很好的相关性。结论:该研究有助于全面了解FA与μOR的相互作用机理和设计新的镇痛化合物。

关 键 词：FENTANYL molecular models solvents binding pocket structure-activity relationship 

分 类 号：R96[医药卫生—药理学]