Steric interactions and the activity of fentanyl analogs at the μ-opioid receptor

Fentanyl is a highly potent and clinically widely used narcotic analgesic. The synthesis of its analogs remains a challenge in the attempt to develop highly selective μ-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking in a study of the formation of complexes between a series of active fentanyl analogs and the μ-opioid receptor is described. The optimal position and orientation of fourteen fentanyl analogs in the binding pocket of the μ-receptor were determined. The major receptor amino acids and the ligand functional groups participating in the complex formation were identified. Stereochemical effects on the potency and binding are explained. The proposed model of ligand–receptor binding is in agreement with point mutation experiments explaining the role of the amino acids: Asp147, Tyr148, Asn230, His297, Trp318, His319, Cys321, and Tyr326 in the complex formation. In addition, the following amino acids were identified as being important for ligand binding or receptor activation: Ile322, Gly325, Val300, Met203, Leu200, Val143, and Ile144.

The interaction mechanism of a series of fentanyl analogs with μ-opioid receptor was studied using flexible molecular docking simulations. Proposed orientations of fentanyl analogs in the binding pocket explain great variation in their enantiospecific potency and binding.Figure optionsDownload as PowerPoint slide