1. Unraveling the Molecular Reason of Opposing Effects of α-Mangostin and Norfluoxetine on TREK-2 at the Same Binding Site.
- Author
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Kim G, Van NTH, Nam JH, and Lee W
- Subjects
- Binding Sites drug effects, Humans, Analgesics pharmacology, Analgesics chemistry, Analgesics chemical synthesis, Molecular Docking Simulation, Structure-Activity Relationship, HEK293 Cells, Molecular Dynamics Simulation, Fluoxetine analogs & derivatives, Xanthones pharmacology, Xanthones chemistry, Xanthones chemical synthesis, Potassium Channels, Tandem Pore Domain metabolism, Potassium Channels, Tandem Pore Domain antagonists & inhibitors, Potassium Channels, Tandem Pore Domain chemistry
- Abstract
TWIK-related K
+ channel (TREK)-2, expressed in sensory neurons, is involved in setting membrane potential, and its modulations contributes to the generation of nociceptive signals. Although acute and chronic pain is a common symptom experienced by patients with various conditions, most existing analgesics exhibit low efficacy and are associated with adverse effects. For this reason, finding the novel modulator of TREK-2 is of significance for the development of new analgesics. Recent studies have shown that α-Mangostin (α-MG) activates TREK-2, facilitating analgesic effects, yet the underlying molecular mechanisms remain elusive. Intriguingly, even though norfluoxetine (NFx) is known to inhibit TREK-2, α-MG is also observed to share a same binding site with NFx, and this implies that TREK-2 might be modulated in a highly complicated manner. Therefore, we examine the mechanism of how TREK-2 is activated by α-MG using computational methods and patch clamp experiments in the present study. Based on these results, we offer an explanation of how α-MG and NFx exhibit opposing effects at the same binding site of TREK-2. These findings will broaden our understanding of TREK-2 modulation, providing clues for designing novel analgesic drugs., (© 2024 The Author(s). ChemMedChem published by Wiley-VCH GmbH.)- Published
- 2024
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