Ensemble-based virtual screening for cannabinoid-like potentiators of the human glycine receptor α1 for the treatment of pain

J Med Chem. 2015 Apr 9;58(7):2958-2966. doi: 10.1021/jm501873p. Epub 2015 Mar 27.


The human glycine receptors (hGlyRs) are chloride-selective ion channels that mediate inhibitory neurotransmission in the brain stem and spinal cord. They are also targets for compounds of potential use in analgesic therapies. Here, we develop a strategy to discover analgesic drugs via structure-based virtual screening based on the recently published NMR structure of the hGlyR-α1 transmembrane domain (PDB ID: 2M6I ) and the critical role of residue S296 in hGlyR-α1 potentiation by Δ(9)-tetrahydrocannabinol (THC). We screened 1549 FDA-approved drugs in the DrugBank database on an ensemble of 180 hGlyR-α1 structures generated from molecular dynamics simulations of the NMR structure of the hGlyR-α1 transmembrane domain in different lipid environments. Thirteen hit compounds from the screening were selected for functional validation in Xenopus laevis oocytes expressing hGlyR-α1. Only one compound showed no potentiation effects; seven potentiated hGlyR-α1 at a level greater than THC at 1 μM. Our virtual screening protocol is generally applicable to drug targets with lipid-facing binding sites.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analgesics, Non-Narcotic / chemistry*
  • Analgesics, Non-Narcotic / pharmacology*
  • Animals
  • Binding Sites
  • Cannabinoids / chemistry*
  • Drug Evaluation, Preclinical / methods*
  • Female
  • Lipids / chemistry
  • Molecular Dynamics Simulation
  • Molecular Targeted Therapy
  • Nuclear Magnetic Resonance, Biomolecular
  • Oocytes / drug effects
  • Pain / drug therapy
  • Protein Conformation
  • Protein Structure, Tertiary
  • Receptors, Glycine / chemistry*
  • Receptors, Glycine / metabolism*
  • Reproducibility of Results
  • Xenopus laevis


  • Analgesics, Non-Narcotic
  • Cannabinoids
  • Lipids
  • Receptors, Glycine