The efficacy of the analgesic GlyT2 inhibitor, ORG25543, is determined by two connected allosteric sites.
allosteric inhibition
analgesic
cholesterol
glycine transporter
molecular dynamics
neuropathic pain
Journal
Journal of neurochemistry
ISSN: 1471-4159
Titre abrégé: J Neurochem
Pays: England
ID NLM: 2985190R
Informations de publication
Date de publication:
22 Dec 2023
22 Dec 2023
Historique:
revised:
23
10
2023
received:
11
09
2023
accepted:
28
11
2023
medline:
22
12
2023
pubmed:
22
12
2023
entrez:
22
12
2023
Statut:
aheadofprint
Résumé
Glycine Transporter 2 (GlyT2) inhibitors have shown considerable potential as analgesics for the treatment of neuropathic pain but also display considerable side effects. One potential source of side effects is irreversible inhibition. In this study, we have characterized the mechanism of ORG25543 inhibition of GlyT2 by first considering three potential ligand binding sites on GlyT2-the substrate site, the vestibule allosteric site and the lipid allosteric site. The three sites were tested using a combination of molecular dynamics simulations and analysis of the inhibition of glycine transport of a series point mutated GlyT2 using electrophysiological methods. We demonstrate that the lipid allosteric site on GlyT2 is the most likely binding site for ORG25543. We also demonstrate that cholesterol derived from the cell membrane can form specific interactions with inhibitor-bound transporters to form an allosteric network of regulatory sites. These observations will guide the future design of GlyT2 inhibitors with the objective of minimising on-target side effects and improving the therapeutic window for the treatment of patients suffering from neuropathic pain.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Health and Medical Research Council
ID : APP1144429
Organisme : National Institute for Drug Abuse, USA
ID : NIH R01DA048879
Informations de copyright
© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.
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