Structure-Based Virtual Screening and Molecular Dynamics Simulation of FDA-Approved Drugs Targeting FGFR3 K650E Mutation in Bladder Cancer

Bladder cancer is one of the most common malignancies of the urinary tract. The most-preferred alterations in bladder cancer include mutations in fibroblast growth factor receptor 3 (FGFR3), primarily the K650E substitution which induces constant activation of FGFR3 kinases and oncogenic signaling. In this study, we are attempting to employ a broad in silico approach combining structure-based virtual screening together with molecular dynamics simulations to repurpose potential FDA-approved drugs for inhibiting the FGFR3 K650E mutant protein. The 3D crystal structure of the mutant (PDB ID: 4K33) was refined and validated using PDB-REDO and SAVES v6.0 tools in order to ensure that the model is geometrically reliable. The FDA-approved compound library was screened through DrugRep, where Irinotecan, Eltrombopag, and Lurasidone came through as top candidates based on docking scores. The protein-ligand complexes were further assessed through normal mode analysis with the iMODS server to study their conformational flexibility along with binding site characteristics and dynamic behavior. The analysis revealed crucial interaction residues along with dynamic hinge regions that affirm strong and biologically plausible molecular binding. The results support a platform for repurposing existing drugs against the FGFR3 K650E variant and provide computational grounds for future experimental validation.