Structure-based virtual screening identifies VX-809 as a candidate dual-pathway modulator in fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is a progressive degenerative disease of the corneal endothelium and remains a leading indication for corneal transplantation worldwide. FECD is characterized by excessive extracellular matrix (ECM) deposition, disruption of proteostasis with endoplasmic reticulum (ER) stress, and progressive endothelial cell loss; however, no pharmacological therapy is currently available. Given that FECD involves multiple interacting pathogenic pathways, we asked whether a structure-based polypharmacology approach could identify a single small molecule capable of modulating distinct disease-relevant targets. We performed 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), which contribute to ECM dysregulation and stress-induced apoptosis. VX-809 was the only compound predicted to bind both targets, with docking scores of - 8.5 kcal/mol for TGF-βR2 and - 10.7 kcal/mol for p38 MAPK; molecular dynamics simulations further supported stable protein-ligand interactions. In patient-derived FECD corneal endothelial cells, VX-809 attenuated TGF-β2-induced apoptosis, suppressed activation of Smad2/3 and p38 MAPK signaling, and reduced ECM overproduction and global protein synthesis. VX-809 also decreased aggresome formation and dampened activation of the PERK, IRE1α, and ATF6 arms of the unfolded protein response, consistent with improved protein homeostasis under stress conditions. Together, these findings show that structure-based screening can reveal previously unrecognized multi-target activities in existing drugs and identify candidate modulators of converging pathogenic pathways in FECD. This study provides proof of concept for docking-based polypharmacology strategies to accelerate early-stage discovery for multifactorial ocular diseases.