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Structure-based virtual screening identifies VX-809 as a candidate dual-pathway modulator in fuchs endothelial
Shunsuke Noda1, Kota Imai1, Taisei Okino1
1Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, 610-0394, Japan.
Scientific Reports
|May 2, 2026
Summary
A novel drug, VX-809, shows promise for treating Fuchs endothelial corneal dystrophy (FECD). This compound targets multiple pathways involved in FECD, reducing cell death and protein buildup, offering hope for a new pharmacological therapy.
Area of Science:
- Ophthalmology
- Pharmacology
- Molecular Biology
Background:
- Fuchs endothelial corneal dystrophy (FECD) is a progressive eye disease causing endothelial cell loss and extracellular matrix deposition.
- Currently, no pharmacological treatments exist for FECD, a leading cause of corneal transplantation.
- FECD pathogenesis involves disrupted proteostasis, endoplasmic reticulum (ER) stress, and apoptosis, suggesting multiple therapeutic targets.
Purpose of the Study:
- To identify a single small molecule capable of modulating distinct, interacting pathogenic pathways in FECD using a structure-based polypharmacology approach.
- To investigate the potential of FDA-approved compounds as multi-target therapeutics for FECD.
Main Methods:
- Virtual screening of 1,178 FDA-approved compounds against transforming growth factor-β receptor type II (TGF-βR2) and p38 mitogen-activated protein kinase (p38 MAPK).
- Molecular docking and dynamics simulations to assess binding affinity and stability of VX-809 to target proteins.
- In vitro studies using patient-derived FECD corneal endothelial cells to evaluate VX-809's effects on apoptosis, signaling pathways, ECM production, and ER stress.
Main Results:
- VX-809 was identified as the sole compound predicted to bind both TGF-βR2 and p38 MAPK.
- VX-809 treatment attenuated TGF-β2-induced apoptosis, suppressed Smad2/3 and p38 MAPK signaling, and reduced ECM overproduction in FECD cells.
- VX-809 decreased aggresome formation and dampened the unfolded protein response, indicating improved protein homeostasis.
Conclusions:
- Structure-based polypharmacology can uncover multi-target activities of existing drugs for complex diseases like FECD.
- VX-809 demonstrates potential as a therapeutic candidate for FECD by simultaneously addressing key pathogenic pathways.
- This study validates a docking-based polypharmacology strategy for accelerating drug discovery in multifactorial ocular diseases.
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