Conformational landscape of selective mu-opioid agonists in gas phase and in aqueous solution: the fentanyl series.

The conformational characteristics responsible for high affinity mu-opioid binding of a series of fentanyl analogs have been investigated using a combination of molecular mechanics and molecular dynamics techniques. In general, the fentanyl analogs favor a conformation that is quite different in gas phase, and in the presence of explicit solvent or lattice packing forces. The most active analogs were shown to possess an extended conformation, while fentanyl derivatives displaying reduced binding affinities are predicted to favor compact arrangements. A superposition of the proposed "bioactive conformations" across this ligand series identified the orientation of the N-phenethyl and the N-phenyl group to be a contributing factor responsible for the differential binding of the ohmefentanyl enantiomers, and other structural analogs. The proposed 3-point pharmacophore model for the fentanyls also provide insights into the structure-activity relationship and serve as a template for further QSAR and docking studies.