Theoretical studies on opioid receptors and ligands. I. Molecular modelingand QSAR studies on the interaction mechanism of fentanyl analogs binding to mu-opioid receptor

Based on our previous result of the three-dimensional model of the mu-opioi d receptor, binding conformations of 13 fentanyl analogs and three-dimensio nal structures for the complexs of these analogs with mu-opioid receptor we re constructed employing the molecular modeling method and our binding conf ormation search program for ligands (BCSPL). Energetic calculation and quan titative structure-activity relationship (QSAR) analysis indicated a good c orrelation between the calculated binding energies of: fentanyl analogs and their binding affinities, pK(i)'s and pK's, and analgesic activities, - lo g ED50's. Based on the threo-dimensional models, the possible interaction m echanism of fentanyl analogs with mu-opioid receptor can be illustrated and the available structure-activity relationship of these analgesic agents ca n be explained reasonably. (C) 2000 John Wiley & Sons, Inc.