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Context <p>The opioid overdose crisis, driven by synthetic opioids like fentanyl, demands a paradigm shift beyond conventional pharmacology. Fentanyl’s lethality stems from its sub-nanomolar affinity and ultra-slow dissociation kinetics from the μ-opioid receptor (μOR), which render competitive antagonists like naloxone increasingly ineffective. This critical limitation necessitates a physics-based strategy capable of directly disrupting the molecular bonds anchoring fentanyl within the receptor’s binding pocket.</p> Method <p>We develop a quantum-mechanical framework to achieve precise, nonthermal disruption of the native fentanyl–μOR complex. Our approach exploits resonant terahertz (THz) near-fields to deliver a Stark perturbation phase-locked to the dominant reaction coordinates: the Asp147 salt-bridge stretch and the His297 hydrogen-bond stretch. The model combines anharmonic Morse potentials for bond stretching with a quantum hindered rotor for ligand torsion, yielding a time-dependent Schrödinger equation with analytic matrix elements. This formalism captures the critical interplay between linear (dipolar) and quadratic (polarizability) Stark effects, which transiently lower the dissociation barrier. We predict dissociation kinetics as a function of field amplitude, frequency, orientation, and pulse duty cycle, establishing a scalable and testable platform for an electromagnetic antidote.</p>

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Resonant terahertz-induced stark field disruption of fentanyl’s μ-opioid receptor binding for precision overdose reversal

  • 期刊论文

  • 发表日期：

    2026年3月17日

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  • Moses Udoisoh,
  • Olusola Olaitan Adegoke,
  • Stephen Nartey Adamtey,
  • Joseph Gyutorwa Samson

摘要

Context

The opioid overdose crisis, driven by synthetic opioids like fentanyl, demands a paradigm shift beyond conventional pharmacology. Fentanyl’s lethality stems from its sub-nanomolar affinity and ultra-slow dissociation kinetics from the μ-opioid receptor (μOR), which render competitive antagonists like naloxone increasingly ineffective. This critical limitation necessitates a physics-based strategy capable of directly disrupting the molecular bonds anchoring fentanyl within the receptor’s binding pocket.

Method

We develop a quantum-mechanical framework to achieve precise, nonthermal disruption of the native fentanyl–μOR complex. Our approach exploits resonant terahertz (THz) near-fields to deliver a Stark perturbation phase-locked to the dominant reaction coordinates: the Asp147 salt-bridge stretch and the His297 hydrogen-bond stretch. The model combines anharmonic Morse potentials for bond stretching with a quantum hindered rotor for ligand torsion, yielding a time-dependent Schrödinger equation with analytic matrix elements. This formalism captures the critical interplay between linear (dipolar) and quadratic (polarizability) Stark effects, which transiently lower the dissociation barrier. We predict dissociation kinetics as a function of field amplitude, frequency, orientation, and pulse duty cycle, establishing a scalable and testable platform for an electromagnetic antidote.