Abstract
OBJECTIVE To build the three-dimensional model of human κ opioid receptor and study its interaction mechanism with antagonist. METHODS The three-dimensional model of κ opioid receptor was built through homology modeling, while the reliability of the model was assessed by Profile-3D analysis and Ramachandran plot. The active site of human κ opioid receptor was searched by DS/Define and Edit Binding Site, and the reasonable active cavity was gained. Then the selective antagonist 5′-GNTI was docked into κ opioid receptor model using CDOCKER. A series of molecular mechanics and dynamics operations were performed to find the most stable binding interaction between 5′-GNTI and the receptor. The "antagonist-bound" receptor model was built and test set antagonists were docked using AutoDock program. RESULTS There was a good linear relationship between ΔG and the experimental affinity lgKi (correlation r=0.779. The ionic interaction was formed between the Asp138 residue at TMⅢ and the protonated amine of different antagonist classes, while the Tyr 139 at TMⅢ, Phe231 and Phe235 at TMV, and Trp287 and His291 at TMVI interacted with the hydrophobic groups or aromatic groups of antagonists with hydrophobic or π-π interaction. CONCLUSION The built receptor model is reasonable and may be used in designing new more active and selective antagonsits. The present study provides a consistent framework for further investigation of the opioid receptor-ligand interaction mechanisms.
Key words
opioid receptor /
homology modeling /
antagonist /
docking
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DING Jun-jie;DING Xio-qin.
Molecular Simulation of κ Opioid Receptor and Antagonist Interaction Mechanism[J]. Chinese Pharmaceutical Journal, 2011, 46(10): 747-752
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