Molecular docking reveals a novel binding site model for fentanyl at the mu-opioid receptor.

Article Details


Subramanian G, Paterlini MG, Portoghese PS, Ferguson DM

Molecular docking reveals a novel binding site model for fentanyl at the mu-opioid receptor.

J Med Chem. 2000 Feb 10;43(3):381-91.

PubMed ID
10669565 [ View in PubMed

The ligand binding modes of a series of fentanyl derivatives are examined using a combination of conformational analysis and molecular docking to the mu-opioid receptor. Condensed-phase molecular dynamics simulations are applied to evaluate potential relationships between ligand conformation and fentanyl substitution and to generate probable "bioactive" structures for the ligand series. Automated docking of the largely populated solution conformers identified a common binding site orientation that places the N-phenethyl group of fentanyl deep in a crevice between transmembrane (TM) helices II and III while the N-phenylpropanamide group projected toward a pocket formed by TM-III, -VI, and -VII domains. An analysis of the binding modes indicates the most potent fentanyl derivatives adopt an extended conformation both in solution and in the bound state, suggesting binding affinity may depend on the conformational preferences of the ligands. The results are consistent with ligand binding data derived from chimeric and mutant receptor studies as well as structure-activity relationship data reported on a wide range of fentanyl analogues. The binding site model is also compared to that of N-phenethylnormorphine. An overlay of the bound conformation of the opiate and cis-3-methylfentanyl shows the N-phenethyl groups occupy equivalent binding domains in the receptor. While the cationic amines of both ligand classes were found docked to an established anchor site (D149 in TM-III), no overlap was observed between the N-phenylpropanamide group and the remaining components of the opiate scaffold. The unique binding mode(s) proposed for the fentanyl series may, in part, explain the difficulties encountered in defining models of recognition at the mu-receptor and suggest opioid receptors may display multiple binding epitopes. Furthermore, the results provide new insight to the design of experiments aimed at understanding the structural basis to the differential selectivities of ligands at the mu-, delta-, and kappa-opioid receptors.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
3-MethylfentanylMu-type opioid receptorProteinHumans
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
3-MethylfentanylKappa-type opioid receptorKi (nM)57.4N/AN/ADetails
3-MethylfentanylMu-type opioid receptorKi (nM)0.02N/AN/ADetails
CarfentanilKappa-type opioid receptorKi (nM)43.1N/AN/ADetails
CarfentanilMu-type opioid receptorKi (nM)0.024N/AN/ADetails
FentanylKappa-type opioid receptorKi (nM)196.5N/AN/ADetails
FentanylMu-type opioid receptorKi (nM)3.97N/AN/ADetails