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<p>The persistent occurrence of cephalosporin antibiotics in aquatic environments raises pressing concerns over environmental toxicity, antimicrobial resistance, and by‑product risks following degradation treatments. Here, we present a multifaceted computational assessment of cefaclor (CFR) degradation by hydroxyl radicals (·OH) under advanced oxidation process (AOP) conditions, integrating density functional theory (DFT) mechanistic mapping, transition‑state kinetic modeling, ecotoxicological prediction (ECOSAR), molecular docking and Molecular dynamics (MD) simulations to DNA. Fukui function analysis identified the most susceptible atomic sites for radical attack, guiding reaction pathway exploration across hydrogen abstraction, ·OH addition, and nucleophilic attack in both neutral and ionized CFR, and in gaseous and aqueous phases. Potential energy surfaces and thermodynamic profiles revealed that hydrogen abstraction dominates, with the lowest Gibbs activation energies (ΔG<sup>≠</sup>as low as 3.48&#xa0;kcal·mol⁻¹) and the highest computed rate constants (up to 2.76 × 10¹⁰ M·s⁻¹ at 298&#xa0;K). In contrast, ·OH addition and nucleophilic attack exhibited higher energy barriers and lower kinetic feasibility. Radical stabilization energy analysis elucidated intermediate persistence, with solvent effects generally decreasing radical stability relative to gas phase. Predicted degradation routes led to seven principal transformation products (P1–P7). ECOSAR toxicity modeling indicated that most products are less toxic than CFR across algae, daphnia, and fish, with the exception of P7 (LC50= 5.57&#xa0;mg·L⁻¹ for daphnia), classified as toxic under GHS criteria. Molecular docking revealed that P1 and P3 exhibit higher DNA-binding affinity than CFR itself (docking scores − 7.6 and − 7.5&#xa0;kcal·mol⁻¹, respectively), suggesting potential genotoxicity despite reduced general aquatic toxicity. By coherently linking reactive site identification, mechanistic energetics, kinetic feasibility, and multi‑trophic ecotoxicological risk within a single integrated framework, this study provides a mechanistically anchored, risk‑aware evaluation of CFR removal via AOPs. The findings not only substantiate AOPs as efficient for rapid CFR degradation, but also highlight the necessity of by‑product bioactivity screening to safeguard environmental and public health. The methodological workflow demonstrated here is broadly transferable to the assessment of other emerging contaminants.</p>

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Computational Investigation of Cefaclor Degradation Mechanism: DFT, By-Product Toxicity, and Molecular Docking Analyses

  • 期刊论文

  • 发表日期：

    2025年11月6日

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  • H. Arab,
  • R. Masmoudi,
  • S. Khettaf,
  • S. Bouchekioua,
  • M. Belloum,
  • A. Dibi,
  • A. Soltani,
  • N. Kenisse,
  • M. Trari,
  • M. Benamira

摘要

The persistent occurrence of cephalosporin antibiotics in aquatic environments raises pressing concerns over environmental toxicity, antimicrobial resistance, and by‑product risks following degradation treatments. Here, we present a multifaceted computational assessment of cefaclor (CFR) degradation by hydroxyl radicals (·OH) under advanced oxidation process (AOP) conditions, integrating density functional theory (DFT) mechanistic mapping, transition‑state kinetic modeling, ecotoxicological prediction (ECOSAR), molecular docking and Molecular dynamics (MD) simulations to DNA. Fukui function analysis identified the most susceptible atomic sites for radical attack, guiding reaction pathway exploration across hydrogen abstraction, ·OH addition, and nucleophilic attack in both neutral and ionized CFR, and in gaseous and aqueous phases. Potential energy surfaces and thermodynamic profiles revealed that hydrogen abstraction dominates, with the lowest Gibbs activation energies (ΔG≠as low as 3.48 kcal·mol⁻¹) and the highest computed rate constants (up to 2.76 × 10¹⁰ M·s⁻¹ at 298 K). In contrast, ·OH addition and nucleophilic attack exhibited higher energy barriers and lower kinetic feasibility. Radical stabilization energy analysis elucidated intermediate persistence, with solvent effects generally decreasing radical stability relative to gas phase. Predicted degradation routes led to seven principal transformation products (P1–P7). ECOSAR toxicity modeling indicated that most products are less toxic than CFR across algae, daphnia, and fish, with the exception of P7 (LC50= 5.57 mg·L⁻¹ for daphnia), classified as toxic under GHS criteria. Molecular docking revealed that P1 and P3 exhibit higher DNA-binding affinity than CFR itself (docking scores − 7.6 and − 7.5 kcal·mol⁻¹, respectively), suggesting potential genotoxicity despite reduced general aquatic toxicity. By coherently linking reactive site identification, mechanistic energetics, kinetic feasibility, and multi‑trophic ecotoxicological risk within a single integrated framework, this study provides a mechanistically anchored, risk‑aware evaluation of CFR removal via AOPs. The findings not only substantiate AOPs as efficient for rapid CFR degradation, but also highlight the necessity of by‑product bioactivity screening to safeguard environmental and public health. The methodological workflow demonstrated here is broadly transferable to the assessment of other emerging contaminants.