Ligand recognition in μ opioid receptor: experimentally based modeling of μ opioid receptor binding sites and their testing by ligand docking

• Published in: Bioorganic & medicinal chemistry 1996-12, Vol.4 (12), p.2151-2166
• Main Authors: Sagara, Takeshi, Egashira, Hiromu, Okamura, Mikako, Fujii, Ikuo, Shimohigashi, Yasuyuki, Kanematsu, Ken
• Format: Article
• Language: English
• Subjects: affinity labelling; Affinity Labels; Amino Acid Sequence; Animals; Aspartic Acid - metabolism; Binding Sites; Brain - metabolism; Computer Simulation; Conserved Sequence; Cysteine - metabolism; Dihydromorphine - chemistry; Dihydromorphine - metabolism; Guinea Pigs; Ileum - chemistry; Ileum - metabolism; ligand recognition; Ligands; Male; Models, Chemical; Models, Molecular; molecular modeling; Molecular Sequence Data; morphine; opioid receptor; Protein Conformation; Receptors, Opioid, mu - chemistry; Receptors, Opioid, mu - metabolism; Sequence Homology, Amino Acid
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(96)00219-2

For three-dimensional understanding of the mechanisms that control potency and selectivity of the ligand binding at the atomic level, we have analysed opioid receptor-ligand interaction based on the receptor's 3D model. As a first step, we have constructed molecular models for the multiple opioid receptor subtypes using bacteriorhodopsin as a template. The S-activated dihydromorphine derivatives should serve as powerful tools in mapping the three-dimensional structure of the μ opioid receptor, including the nature of the agonist-mediated conformational change that permits G protein-coupling to ‘second messenger’ effector molecules, and in identifying specific ligand-binding contacts with the μ opioid receptor. The analyses of the interactions of some opioid ligands with the predicted ligand binding sites are consistent with the results of the affinity labeling experiments. For three-dimensional understanding of the mechanisms that control potency and selectivity of the ligand binding at the atomic level, we have analysed the feature of the opioid receptor-ligand interaction based on the receptor's 3-D model using the S-activated dihydromorphine derivative (ligands 1 and 2).