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

SUBMITTER: Wells MM 

PROVIDER: S-EPMC4414066 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature