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

Abstract
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.
AuthorsMarta M Wells, Tommy S Tillman, David D Mowrey, Tianmo Sun, Yan Xu, Pei Tang
JournalJournal of medicinal chemistry (J Med Chem) Vol. 58 Issue 7 Pg. 2958-2966 (Apr 09 2015) ISSN: 1520-4804 [Electronic] United States
PMID25790278 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Analgesics, Non-Narcotic
  • Cannabinoids
  • Lipids
  • Receptors, Glycine
Topics
  • Analgesics, Non-Narcotic (chemistry, 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, metabolism)
  • Reproducibility of Results
  • Xenopus laevis

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