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