Dual-site TAS2R14 binding by (-)-epicatechin gallate: A computational framework for neuroprotective drug repurposing
Armin Sultana1, Raju Das2, JooHan Woo3
1Department of Physiology, College of Medicine, Dongguk University Wise, Gyeongju, 38066, Republic of Korea.
Journal of Molecular Graphics & Modelling
|August 6, 2026
Summary
This study computationally screened FDA-approved drugs to find new TAS2R14 ligands for neurodegenerative disorders. (-)-epicatechin gallate, fexofenadine, and ezetimibe showed promising binding stability for potential therapeutic repositioning.
Area of Science:
- Neuropharmacology and Computational Drug Discovery
- Bitter Taste Receptor (TAS2R) Research
Background:
- Bitter taste receptors (TAS2Rs), including TAS2R14, are present in the central nervous system and linked to neuroinflammation and neurodegeneration.
- Existing therapies for neurodegenerative diseases are limited, highlighting the need for novel therapeutic targets and drug repositioning strategies.
Purpose of the Study:
- To identify potential TAS2R14 ligands among FDA-approved drugs for therapeutic repositioning against neurodegenerative disorders.
- To investigate the binding modes and stability of identified ligands at both extracellular and intracellular TAS2R14 binding sites using computational methods.
Main Methods:
- Structure-based virtual screening of 4138 FDA-approved drugs against TAS2R14.
- Hierarchical molecular docking, MM-GBSA binding free-energy calculations, GNINA validation, ADMET assessment, and 500 ns molecular dynamics simulations.
- Analysis of ligand-receptor interactions, conformational dynamics, and binding stability.
Main Results:
- Identified (-)-epicatechin gallate, fexofenadine, and ezetimibe as promising TAS2R14 ligands with distinct binding profiles at extracellular and intracellular sites.
- (-)-epicatechin gallate demonstrated favorable and persistent interactions at both sites, suggesting potential dual-site binding.
- Fexofenadine and ezetimibe showed favorable binding stability at the extracellular and intracellular sites, respectively, outperforming reference ligands in simulations.
Conclusions:
- This computational study provides a foundation for prioritizing TAS2R14 ligands for neuroprotection, with (-)-epicatechin gallate being a key candidate for further investigation.
- The findings support experimental validation to confirm the functional modulation of TAS2R14 by these compounds and their therapeutic efficacy in neurodegenerative contexts.
- Drug repositioning targeting TAS2R14 offers a promising avenue for developing novel disease-modifying therapies for neurodegenerative disorders.
