Determination of structure-activity relationships between fentanyl analogs and human μ-opioid receptors based on active binding site models

作     者：Ming Liu Xiaoli Liu Ping Wan Qiangsan Wu Wenxiang Hu 

作者机构：College of Life Science Capital Normal University Beijing 100048 China Department of Chemistry Capital Normal University Beijing 100048 China 

出 版 物：《Neural Regeneration Research》 (中国神经再生研究（英文版）)

年 卷 期：2011年第6卷第4期

页      面：267-276页

核心收录：

学科分类：0710[理学-生物学] 12[管理学] 1201[管理学-管理科学与工程(可授管理学、工学学位)] 07[理学] 071003[理学-生理学] 

基　　金：supported by the National Natural Science Foundation of China(Molecular design catalysis and synthesis methods of novel fentanyl analogs active compounds)No.20872095 

主　　题：μ-opioid receptor fentanyl analogs agonist active site structure-activity relationship 

摘      要：Fentanyl is a potent and widely used clinical narcotic analgesic, as well as a highly selective IJ-opioid agonist. The present study established a homologous model of the human μ-opioid receptor; an intercomparison of three types of μ-opioid receptor protein sequence homologous rates was made. The secondary receptor structure was predicted, the model reliability was assessed and verified using the Ramachandran plot and ProTab analysis. The predictive ability of the CoMFA model was further validated using an external test set. Using the Surflex-Dock program, a series of fentanyl analog molecules were docked to the receptor, the calculation results from Biopolymer/SitelD showed that the receptor had a deep binding area situated in the extracellular side of the transmembrane domains （TM） among TM3, TM5, TM6, and TMT. Results suggested that there might be 5 active areas in the receptor. The important residues were Asp147, Tyr148, and Tyr149 in TM3, Trp293, and His297 in TM6, and Trp318, His319, Ile322, and Tyr326 in TM7, which were located at the 5 active areas. The best fentanyl docking orientation position was the piperidine ring, which was nearly perpendicular to the membrane surface in the 7 TM domains. Molecular dynamic simulations were applied to evaluate potential relationships between ligand conformation and fentanyl substitution.