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.
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Authors | Marta M Wells, Tommy S Tillman, David D Mowrey, Tianmo Sun, Yan Xu, Pei Tang |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 58
Issue 7
Pg. 2958-2966
(Apr 09 2015)
ISSN: 1520-4804 [Electronic] United States |
PMID | 25790278
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Analgesics, Non-Narcotic
- Cannabinoids
- Lipids
- Receptors, Glycine
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Topics |
- Analgesics, Non-Narcotic
(chemistry, pharmacology)
- Animals
- Binding Sites
- Cannabinoids
(chemistry)
- Drug Evaluation, Preclinical
(methods)
- Female
- Lipids
(chemistry)
- Molecular Dynamics Simulation
- Molecular Targeted Therapy
- Nuclear Magnetic Resonance, Biomolecular
- Oocytes
(drug effects)
- Pain
(drug therapy)
- Protein Conformation
- Protein Structure, Tertiary
- Receptors, Glycine
(chemistry, metabolism)
- Reproducibility of Results
- Xenopus laevis
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