title: 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.
authors: Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261.|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261.
authors: Marta M
authors: MM
authors: Wells
authors: Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261.
authors: Tommy S
authors: TS
authors: Tillman
authors: Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261.
authors: David D
authors: DD
authors: Mowrey
authors: Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261.
authors: Tianmo
authors: T
authors: Sun
authors: Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261.|Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15261.|Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261.
authors: Yan
authors: Y
authors: Xu
authors: Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261.|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261.|Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261.
authors: Pei
authors: P
authors: Tang
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002186:Cannabinoids / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D008055:Lipids / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D019906:Nuclear Magnetic Resonance, Biomolecular; D009865:Oocytes / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018009:Receptors, Glycine / Q000737:chemistry* / Q000378:metabolism*; D015203:Reproducibility of Results; D014982:Xenopus laevis
chemical_list: D018712:Analgesics, Non-Narcotic; D002186:Cannabinoids; D008055:Lipids; D018009:Receptors, Glycine