In silico Repurposing of FDA-approved Drugs to Inhibit Ran GTPase in Breast Cancer

Introduction: Breast cancer continues to be a major health burden worldwide, with treatment resistance and tumor recurrence posing significant challenges. Ran GTPase, a key regulator of nucleocytoplasmic transport and mitosis, is frequently overexpressed in breast cancer and has emerged as a potential therapeutic target. Methods: This study employed a drug repurposing approach to identify FDA-approved com-pounds capable of inhibiting Ran GTPase using high-throughput virtual screening, molecular docking, molecular dynamics simulations, DFT, and ADME &T analysis. Results: Guadecitabine, Folic Acid, Mln-8054, and Fluvastatin were identified through bind-ing energy and interaction profiles. Folic Acid and Fluvastatin showed structural stability and interaction throughout 100 ns simulations compared to others. This was further supported by RMSD, RMSF, and hydrogen bond analyses. The reactivity and stability of the complexes were determined through frontier molecular orbital analysis. Additionally, the molecular elec-trostatic potential (MEP) was evaluated to identify electrophilic and nucleophilic reactive sites. Discussion: Based on virtual screening, four compounds were identified for further validation. 2D and 3D interaction diagrams were created to assess the binding profiles. A 100ns MD simulation was performed to evaluate the stability and conformational behavior of the protein-ligand complexes. Further, two lead compounds were considered based on DFT calculation and ADMET profiling. To determine the translational value of the identified compounds, ex-perimental validation is required, which would include quantitative binding measurements us-ing SPR and ITC and Ran GTPase-dependent assays to study their effect on target pathway activity. Also, in vivo studies in breast cancer models will prove their antitumor activity, phar-macokinetics, and tolerability, providing a foundation for future therapeutic development. Conclusion: These findings suggest that repurposed FDA-approved drugs may offer a viable route for targeting Ran GTPase in breast cancer, warranting further experimental validation and therapeutic development.