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