期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 7, 页码 2958-2966出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm501873p
关键词
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资金
- National Science Foundation [TG-MCB050030N]
- NIH [T32EB009403, R01GM066358, R01GM056257, R37GM049202]
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.
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