An Insight for Interaction Between Dinotefuran and Acetylcholinesterase: Docking, Molecular Dynamics Simulations, PCA, and DFT Calculations

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Neonicotinoid insecticides such as dinotefuran are widely used in pest control due to their strong systemic activity and proven effectiveness in managing a broad range of agricultural pests. However, their potential harm to non‐target organisms raises serious concerns about ecological safety and biodiversity. In this study, in silico approach was used to investigate the interactions between dinotefuran and acetylcholinesterase (AChE) in zebrafish ( Danio rerio ) a key model organism for toxicological research. To explore these interactions, homology modeling was used to construct the 3D structure of zebrafish AChE, which was validated through quality assessment tools such as Procheck, ERRAT and Verify 3D. Molecular docking analysis showed that dinotefuran binds to the active site of AChE, interacting with key residues Tyr146, Tyr355 and Trp108, with a binding energy of −6.8 kcal/mol. ADMET profiling indicated favorable pharmacokinetic properties such as good gastrointestinal absorption and bioavailability, while also suggesting minimal central nervous system involvement due to the compound limited blood‐brain barrier permeability. Additionally, Density functional theory (DFT) calculations provided insights into the electronic properties of dinotefuran, showing a reduced HOMO‐LUMO gap and increased thermodynamic stability of the dinotefuran with amino acid residues of AChE. Molecular dynamics simulations further confirmed the stability of this complex and revealed structural changes in AChE indicating potential disruptions to its normal function. These findings contribute to a deeper understanding of the molecular mechanisms underlying dinotefuran toxicity and its impact, providing a valuable framework for assessing the risks associated with its agricultural use.