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.
Marta M Wells   #  1  2 ,  Tommy S Tillman   #  1 ,  David D Mowrey  1 ,  Tianmo Sun  1 ,  Yan Xu  1  3  4 ,  Pei Tang  1  2  4
Affiliations
  • 1. Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261.
  • 2. Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261.
  • 3. Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15261.
  • 4. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261.
  • # Contributed equally.
PMID: 25790278 DOI: 10.1021/jm501873p
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.

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