Dual-site TAS2R14 binding by (-)-epicatechin gallate: A computational framework for neuroprotective drug repurposing

Bitter taste receptors, particularly TAS2R14, are widely expressed in extraoral tissues, including the central nervous system, where they have been implicated in neuroinflammatory and neurodegenerative processes. Although numerous pharmacological and natural compounds have demonstrated therapeutic potential against neurodegenerative disorders, clinically effective disease-modifying therapies remain strikingly limited. TAS2R14 is a promising yet underexplored candidate target; however, its mechanistic role in neurodegenerative disorders remains poorly understood. Here, we conducted a structure-based virtual screening of 4138 FDA-approved drugs from the MedChemExpress database to identify potential TAS2R14 ligands for therapeutic repositioning. Top candidates were prioritized through a hierarchical molecular docking workflow and binding free-energy calculations (MM-GBSA), orthogonal GNINA validation, in silico ADMET assessment, followed by 500 ns molecular dynamics (MD) simulations to evaluate the persistence of predicted binding modes and ligand-associated conformational behavior at both extracellular and intracellular binding sites. The selected hits exhibited distinct predicted interaction profiles and conformational dynamics at the two independent binding sites. Among them, (-)-epicatechin gallate exhibited favorable interactions, persistent contact with key binding site residues, and comparatively limited conformational fluctuations at both sites, supporting its prioritization as a potential dual-site TAS2R14 binder. Furthermore, fexofenadine and ezetimibe showed favorable binding stability at the extracellular and intracellular sites, respectively. Hydrogen-bond analysis, principal component analysis, dynamic cross-correlation matrix analysis, and free-energy landscape mapping further revealed ligand-dependent differences in interaction networks and receptor conformational behavior. Notably, (-)-epicatechin gallate, fexofenadine, and ezetimibe exhibited greater predicted binding stability than the reference ligands flufenamic acid, cholesterol, and Comp28.1 throughout the 500 ns simulations. As this study is purely computational, experimental validation through receptor activation assays and relevant biological models will be required to determine whether the predicted binding interaction translates into functional modulation of TAS2R14 and therapeutic benefit. Nevertheless, these findings provide a computational foundation for prioritizing candidate TAS2R14 ligands and support future experimental studies to evaluate receptor activation, specificity, selectivity, and therapeutic efficacy, particularly for (-)-epicatechin gallate, in the context of TAS2R14-targeted neuroprotective drug repositioning.