Abstract��
OBJECTIVE To build the three-dimensional model of human �� opioid receptor and study its interaction mechanism with antagonist. METHODS The three-dimensional model of �� 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 �� 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 �� 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 ��G and the experimental affinity lgKi (correlation r=0.779. The ionic interaction was formed between the Asp138 residue at TM�� and the protonated amine of different antagonist classes�� while the Tyr 139 at TM�� Phe231 and Phe235 at TMV�� and Trp287 and His291 at TMVI interacted with the hydrophobic groups or aromatic groups of antagonists with hydrophobic or ��-�� 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.
2011, Vol. 46 