PhD Scientific Days 2026

Poster Session 3.J - Theoretical and Translational Medicine

In silico investigation of photoactivatable VEGFR2 inhibitor EYE1118 for targeted therapy of retinal neovascular diseases

Name of the presenter

Szappanos, Attila

Institute/workplace of the presenter

Institute of Clinical Pathophysiology

Authors

Attila Szappanos¹, Balázs Besztercei¹, Réka Antal¹, Dr. Krisztián András Kovács¹
1: Institute of Clinical Pathophysiology

Text of the abstract

In late-stage age-related macular degeneration (AMD) and diabetic retinopathy (DR), the excessive, VEGF mediated retinal angiogenesis causes rapid vision loss. Current therapy requires intravitreal injections, that carry side effects, need medical professionals for administration and decrease patient compliance.
The NeoVasculoStop project aims to create a per os medicine, selectively targeted to the eye, to minimise systemic side effects of angiogenesis inhibitors. The developed molecules would be activated by light naturally reaching the retina, thus acting nearly exclusively on retinal VEGFR2. Upon activation, the azidated molecules would bind covalently to the receptor, enabling high local efficacy at low systemic concentrations. Our lead compound, EYE1118 proved to be an effective and photoactivatable inhibnitor in luciferase assays and in vitro angiogenesis experiments, with its potency increasing when exposed to light. However, the exact reaction mechanism between the light sensitive inhibitor and the receptor is yet to be examined. Therefore, we aimed to model EYE1118 in silico to discover its interaction with its receptor.
EYE1118 and VEGFR2 structures were prepared with AutoDockTools, and docking was performed using AutoDock Vina. Binding interactions were analyzed in PyMOL. For molecular dynamics, EYE1118 was parameterized using the Force-Field Toolkit (FFTK) in VMD-NAMD, supported by quantum chemical calculations in ORCA to derive geometry, charges, and bonded parameters.
Docking results show that EYE1118 binds in the ATP-binding pocket similarly to known VEGFR2 inhibitors (sunitinib, vorolanib), and with comparable binding energy. It forms hydrogen bonds with Glu917 and Cys919. Importantly, the azido group is positioned near Lys868, suggesting the accessibility of this residue for covalent bond formation upon photoactivation.
Molecular docking revealed key interactions and a potential interaction with the ε-amino group of Lys868. Ongoing molecular dynamics studies will clarify the photoactivation process and binding behavior. A deeper understanding of the photoactivation process and the potential covalent binding to VEGFR2 could validate EYE1118 as a novel, light-activated therapeutic molecule against DR and AMD.
Funding: European Commission via an EIC Pathfinder grant (Grant No: 101047120); SE250+ PhD Excellence Grant by Semmelweis University.