Ensemble-Based Virtual Screening
for Cannabinoid-Like
Potentiators of the Human Glycine Receptor α1 for the Treatment
of Pain
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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<sup>9</sup>-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