A putative binding model of nitazene derivatives at the μ-opioid receptor

This is the authors' abstract. We don't add key points for this paper.

Nitazenes are a class of novel synthetic opioids with exceptionally high potency. Currently, an experimental structure of μ OR-opioid receptor ( μ OR) in complex with a nitazene is lacking. Here we used a suite of computational tools, including consensus docking, conventional molecular dynamics (MD) and metadynamics simulations, to investigate the μ OR binding modes of nitro-containing meto-, eto-, proto-, buto-, and isotonitazenes and nitro-less analogs, metodes-, etodes-, and protodesnitazenes. Docking generated three binding modes, whereby the nitro-substituted or unsubstituted benzimidazole group extends into SP1 (subpocket 1 between transmembrane helix or TM 2 and 3), SP2 (subpocket 2 between TM1, TM2, and TM7) or SP3 (subpocket 3 between TM5 and TM6). Simulations suggest that etonitazene and likely also other nitazenes favor the SP2-binding mode. Comparison to the experimental structures of μ OR in complex with BU72, fentanyl, and mitragynine pseudoindoxyl (MP) allows us to propose a putative model for μ OR-ligand recognition in which ligand can access hydrophobic SP1 or hydrophilic SP2, mediated by the conformational change of Gln124 2.60 . Interestingly, in addition to water-mediated hydrogen bonds, the nitro group in nitazenes forms a π-hole interaction with the conserved Tyr75 1.39 . Our computational analysis provides new insights into the mechanism of μ OR-opioid recognition, paving the way for investigations of the structure-activity relationships of nitazenes. • Molecular docking generated three potential binding modes of nitazenes at mu-opioid receptor (muOR). • Molecular dynamics simulations suggest that etonitazene positions the benzimidazole group in subpocket 2 (SP2). • We propose that muOR-ligand recognition occurs through alternating access to hydrophilic SP1 or hydrophobic SP2.