Mechanism-based QSAR and molecular simulation reveal the toxicity of marine disinfection byproducts to Vibrio fischeri

Intensified disinfectant use since the COVID-19 pandemic has increased the occurrence of disinfection byproducts (DBPs) in aquatic environments, raising concerns about their ecological effects. In this study, we evaluated the acute toxicity of 23 representative DBPs to the marine bacterium Vibrio fischeri ( V. fischeri ), including quinone DBPs (Q-DBPs), phenolic DBPs (P-DBPs), and haloacetic acids (HAAs). Toxicity followed the order Q-DBPs > P-DBPs > HAAs and was further influenced by halogenation patterns, solubility, and lipophilicity. Excess toxicity analysis indicated that Q-DBPs mainly act through electrophilic and redox reactions, whereas HAAs primarily undergo nucleophilic substitution (SN2). Molecular docking and molecular dynamics simulations suggested that DBPs interact with multiple proteins in V. fischeri , with the quorum-sensing regulator LuxR proposed as a potential target contributing to luminescence inhibition. Based on these mechanistic insights, we developed mechanism-based QSAR models that integrated molecular descriptors with receptor-binding parameters. The models showed strong predictive power (R² = 0.917, Q² = 0.798) and mechanistic interpretability. LuxR binding energy, ionization (pKa), and electronic reactivity (E HOMO ) were key determinants of P-DBP and HAA toxicity. In contrast, Q-DBPs toxicity was mainly associated with electronic reactivity consistent with electrophilic and redox behavior. • Acute toxicity of 23 disinfection by-products (DBPs) to Vibrio fischeri was evaluated. • Aromatic DBPs showed much higher toxicity than aliphatic haloacetic acids. • Excess toxicity revealed electrophilic and redox-driven mechanisms for Q-DBPs. • LuxR proposed as a potential target contributing to luminescence inhibition. • Mechanism-based QSAR linked LuxR binding, pKa, and E HOMO to DBP toxicity.