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Author Spotlight: An Efficient Methodology to Confidently Differentiate and Characterize Fentanyl Analogs
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How μ-opioid receptor recognizes fentanyl

Quynh N Vo1,2, Paween Mahinthichaichan1,2, Jana Shen3

  • 1Center for Drug Evaluation and Research, United State Food and Drug Administration, Silver Spring, MD, USA.

Nature Communications
|February 13, 2021
PubMed

Insights

Fentanyl, a synthetic opioid, binds to the mu-opioid receptor (mOR) through a unique mechanism. This binding involves a secondary hydrogen bond with His297, offering new insights into opioid receptor activation.

Area of Science:

  • Pharmacology
  • Structural Biology
  • Medicinal Chemistry

Background:

  • Synthetic opioids like fentanyl are major contributors to drug overdose deaths in the US.
  • Fentanyl is a potent agonist of the mu-opioid receptor (mOR).
  • Structural data on fentanyl-like opioid binding to mOR is limited.

Purpose of the Study:

  • To elucidate the detailed binding mechanism of fentanyl to the mu-opioid receptor (mOR).
  • To understand the structural basis of mOR activation by fentanyl-like opioids.

Main Methods:

  • Utilized X-ray crystal structure of BU72-bound mOR.
  • Employed molecular simulation techniques.
  • Analyzed binding modes and interactions.

Main Results:

  • Fentanyl exhibits a unique binding mechanism at the mOR.
  • Beyond the common salt-bridge, fentanyl forms a stable hydrogen bond with His297.
  • This secondary binding mode requires His297 to be in a neutral HID tautomer.
  • His297 is implicated in modulating mOR ligand affinity and pH dependence.

Conclusions:

  • Fentanyl's binding mechanism at mOR is distinct from morphinan opiates.
  • A secondary binding mode involving His297 offers new insights into mOR activation.
  • Alternative binding modes may be a general principle in G protein-coupled receptor-ligand interactions.

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