Network toxicology and molecular docking reveal key mechanisms of domoic acid neurotoxicity with bio-layer interferometry validation

Abstract

The study aims to promote a network toxicology strategy to efficiently investigate the underlying neurotoxicity molecular mechanisms of domoic acid（DA）, which is one of the main toxins of paralytic amnesic shellfish poisoning and has gained significant attention due to its ability to induce neurotoxicity. By utilizing ChEMBL, CTD, Drug bank, TTD, DGIdb, Pharmapper and GeneCards databases, we identified 73 potential targets associated with DA-exposure related amnesia and neurotoxicity. Further refinements via STRING and Cytoscape software highlight the protein-protein interactions. 30 targets were recognized by both the K-means algorithm and topological analysis. GO and KEGG pathway analysis conducted through DAVID databases reveals that these targets of amnesia and neurotoxicity are predominantly enriched in multiple pathways. AKT1 was identified by a multiple-topically methods as the key target. Molecular docking and bio-layer interferometry were conducted to confirm the binding between these targets and DA(-CDOCKER_INTERACTION_ENERGY =45.719 kcal/mol, KD=2.0E-11M). This research provides a theoretical basis for understanding the molecular mechanism of DA-induced neurotoxicity, as well as establishing a foundation for the prevention and treatment of DA exposure.

Keywords

• Domoic acid
• Brain injury
• Amnesia
• Network toxicology
• Molecular docking
• Bio-layer interferometry