Drug repurposing study of levofloxacin: Structural properties, lipophilicity along with experimental and computational DNA binding

The process of developing new drug molecules is often lengthy, costly and labor-intensive, requiring several years to progress through clinical trials. However, in recent years, drug repurposing has emerged as a popular approach due to its ability to expedite the drug discovery process. By repurposing existing drugs for new therapeutic uses, valuable time and resources can be saved. Antibiotics, particularly fluoroquinolones have been reported to exhibit antitumor effects by reducing tumor growth and inducing cell cycle arrest. These antibiotics may disrupt specific cellular mechanisms, offering a potential avenue for novel anticancer treatments. Levofloxacin, a fluoroquinolone antibiotic, has a broad spectrum of action against certain bacteria, but its efficacy against most anaerobic bacteria is generally limited. In this study, the structural assessment and joint experimental – theoretical investigation was performed on its DNA binding ability mainly in molecular level from thermodynamics and mechanistic points of view. These include determining stability, charge delocalization, softness, reactivity and electrophilicity indices. Promising results were found in the assessment of this compound lipophilicity and stability. In addition, its interaction with DNA was investigated using both experimental analyses and molecular modeling techniques including molecular docking, molecular dynamics simulation and DFT via ONIOM procedure, demonstrating its binding to the minor groove of DNA through van der Waals/hydrogen bond forces. Based of experimental results, levofloxacin quenches the fluorescence of DNA through a static mechanism with the negative values for ΔH° and ΔS° thermodynamics quantities. Furthermore, one binding site on each DNA with 1000 nucleotides is available for each levofloxacin molecule.