Redesigning Fluoroquinolones: A Hybrid Strategy to Reduce Cardiotoxicity and Enable Neuroprotective Repurposing

Fluoroquinolones are recognized widely for their efficacies against bacterial infection, as they are mainly associated with QT interval prolongation due to the inhibition of the hERG potassium channels. Although repurposing of drug development offers cost-effective therapeutic opportunities, the mechanistic role of off-target effects is poorly understood which requires further exploration. Our study computationally integrated the leveraging framework of pharmacophore modeling, free energy estimations, and molecular dynamics simulations to enhance fluoroquinolone derivatives for their better antibacterial potency while mitigating cardiotoxicity. Binding studies demonstrated that moxifloxacin engages deeply within the hERG channel’s inner cavity, primarily stabilized by van der Waals attractions and cation-π interactions with key residues TYR545, PHE551, and ARG541. Structural refinements lowered hERG channel binding affinity by ≥1.7 kcal/mol and enhanced predicted LD₅₀ values by over 80%, all while retaining antibacterial potency. The designed polar modification served dual purposes: (1) electronically perturbating of the TYR545 aromatic system and (2) conservation of the pharmacologically essential interactions with gyrase's catalytic pocket and divalent cation. Cross-conformational docking analysis revealed persistent pharmacophore compatibility and binding site plasticity between 5CDR and 2XCT gyrase states, highlighting the mechanistic importance of conserved hydration-shell interactions and charge-based stabilization in molecular recognition. _Structural derivatives transitioned from toxicity Class IV to Class VI in _silico simulations showing favorable oral bioavailability, supported by predictive ADMET modeling and reduced CYP450 interactions. Mechanistic profiling of off-label therapeutics in non-infectious disease models identified high-affinity interactions and robust dynamic stability with key inflammatory regulators MAPK14 and NLRP3. The therapeutic expansion of multi-indication fluoroquinolones with improved safety profiles and computational modeling highlighted the drug's repositioning potential for CNS inflammatory diseases, setting the stage for preclinical validation and scaffold transformation.