How μ-opioid receptor recognizes fentanyl

Abstract

Roughly half of the drug overdose-related deaths in the United States are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid receptor (mOR). In recent years, X-ray crystal structures of mOR in complex with morphine derivatives have been determined; however, structural basis of mOR activation by fentanyl-like opioids remains lacking. Exploiting the X-ray structure of BU72-bound mOR and several molecular simulation techniques, we elucidated the detailed binding mechanism of fentanyl. Surprisingly, in addition to the salt-bridge binding mode common to morphinan opiates, fentanyl can move deeper and form a stable hydrogen bond with the conserved His2976.52, which has been suggested to modulate mOR’s ligand affinity and pH dependence by previous mutagenesis experiments. Intriguingly, this secondary binding mode is only accessible when His2976.52 adopts a neutral HID tautomer. Alternative binding modes may represent a general mechanism in G protein-coupled receptor-ligand recognition.

Kinetics and Mechanism of Fentanyl Dissociation from theµ-Opioid Receptor

“…7 The second set of simulations comprised of 15 independent metadynamics runs for each protonation state was initiated from the most populated configuration of the fentanyl-mOR complex from the recent 40- µ s weighted-ensemble (WE) simulations. 16 In this structure, fentanyl also forms a salt-bridge with D147 3.32 but the COM z is about 1 Å. Note, the C α z of D147 3.32 was stable in the simulations (e.g., standard deviation of 0.3 Å in the Hid trajectories).…”

“…1b), and the piperidine-D147 3.32 binding mode has been recently validated by molecular docking 13 and molecular dynamics (MD) simulations. 14–16 Nonetheless, fentanyl and morphine differ significantly in their structures and signaling biases, which has been speculated as a result of different binding and activation mechanisms. 5…”

“…Using multiple MD techniques including the continuous constant pH and weighted-ensemble (WE) methods, 16 we recently found that fentanyl can adopt a secondary binding mode through hydrogen bonding between the piperidine and the conserved H297 6.52 on TM6. Intriguingly, the H297-binding mode only occurred in the simulations with the N δ -protonated state.…”

“…Intriguingly, the H297-binding mode only occurred in the simulations with the N δ -protonated state. 16 The protonation state of H297 6.52 has been repeatedly suggested as important for mOR’s ligand recognition and activity; however, the precise role of H297 6.52 remains unclear. Mutagenesis experiments showed that at low pH whereby H297 6.52 is likely protonated, mOR’s affinities for DAMGO and naloxone are reduced; 12,17 however, the measurement conducted with fentanyl was inconclusive.…”

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

“…Indeed, they have been reported as one of the main causes of the waves of opioid deaths in the USA [ 9 , 10 , 11 , 12 , 13 ]. The term “synthetic opioids” includes a wide range of antinociceptive and analgesic compounds (fentanyl derivatives, benzamide, acetamide and piperazine families) [ 14 ] that act as partial or full agonists at G-protein-coupled receptors (μ, κ, and δ) [ 15 , 16 , 17 ]. μ-opioid receptors, as shown in knock-out mice, are mainly located in brain and gastrointestinal tract and lead to anxiolysis, relaxation, sedation, antinociception, euphoria, and respiratory depression [ 7 , 17 , 18 , 19 , 20 , 21 ].…”