Ensemble-Based Virtual Screening for Cannabinoid-Like Potentiators of the Human Glycine Receptor α1 for the Treatment of Pain

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-alpha 1 transmembrane domain (PDB ID: 2M6I) and the critical role of residue S296 in hGlyR-alpha 1 potentiation by Delta(9)-tetrahydrocannabinol (THC). We screened 1549 FDA-approved drugs in the DrugBank database on an ensemble of 180 hGlyR-alpha 1 structures generated from molecular dynamics simulations of the NMR structure of the hGlyR-alpha 1 transmembrane domain in different lipid environments. Thirteen hit compounds from the screening were selected for functional validation in Xenopus laevis oocytes expressing hGlyR-alpha 1. Only one compound showed no potentiation effects; seven potentiated hGlyR-alpha 1 at a level greater than THC at 1 mu M. Our virtual screening protocol is generally applicable to drug targets with lipid-facing binding sites.