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Molecular basis for anti-insomnia drug design from structure of lemborexant-bound orexin 2 receptor

Hidetsugu Asada1, Dohyun Im1, Yunhon Hotta1

  • 1Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.

Structure (London, England : 1993)
|November 23, 2022
PubMed

Insights

Researchers determined the structure of the OX2R bound to lemborexant, a dual orexin receptor antagonist. This provides insights into controlling molecular binding for novel insomnia treatments.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Structural Biology

Background:

  • Orexin receptors (OX1Rs and OX2Rs) are G protein-coupled receptors crucial for regulating the sleep-wake cycle.
  • Modulation of orexin receptors is a key target for developing treatments for sleep disorders like insomnia.

Purpose of the Study:

  • To determine the high-resolution structure of the OX2 receptor bound to lemborexant.
  • To analyze the binding properties of dual orexin receptor antagonists (DORAs).

Main Methods:

  • X-ray crystallography was used to determine the structure of OX2R bound to lemborexant at 2.89 Å resolution.
  • Kinetic and dynamic simulations were employed to compare DORA properties.

Main Results:

  • The study determined the crystal structure of OX2R in complex with lemborexant.
  • Comparisons of kinetic and dynamic properties suggest independent control over binding enthalpy and intramolecular entropy for DORAs.

Conclusions:

  • The determined structure provides valuable insights into OX2R-DORA interactions.
  • Findings support the potential for designing selective orexin receptor antagonists by controlling binding thermodynamics and molecular dynamics.
Keywords:
G protein-coupled receptorX-ray crystallographyanti-insomnia drugmolecular dynamicsorexin-2 receptor

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