Exploring Natural Compounds as Multitarget Inhibitors of Botulinum Neurotoxin: Insights from Molecular Docking Analyses

For the first time, this communication is intended to perform the possible biological role of natural compounds in the crystal structure of botulinum neurotoxin (BoNT), a protein produced by the bacterium Clostridium botulinum. This is among the most potent biological toxins. It causes botulism, a serious illness, and represents a major public health concern. Developing natural inhibitors that can safely neutralize BoNT’s toxic effects is particularly appealing due to their low risk of adverse effects and therapeutic potential. In this study, we used molecular docking—a computational method to predict how molecules interact—to screen 50 naturally occurring compounds against multiple functional regions of BoNT/A. These regions included the catalytic domain, which mediates the cleavage of target proteins, and the receptor-binding domain, which facilitates the toxin’s attachment to neuronal cells. Predicted binding affinities, expressed in kilocalories per mole (kcal/mol) and calculated using AutoDock Vina, indicated that several plant-derived compounds exhibited strong interactions across different target sites. In particular, Hypericin (–10.0 kcal/mol), Hesperidin (–10.8 kcal/moland Silibinin (–10.1 kcal/mol) emerged as top multitarget lead compounds, demonstrating notable binding potential. Additional compounds, including Baicalin, Epicatechin Gallate, Scutellarin, Naringin, and Rutin, demonstrated strong binding specifically to the catalytic site, reinforcing the value of polyphenols and flavonoids as versatile scaffolds.These results highlight the promise of natural compounds as safe and effective BoNT inhibitors and provide a solid basis for future experimental validation and drug repurposing efforts. Overall, Hypericin emerged as the top candidate for disrupting BoNT/A activity due to its consistently high binding across receptor-binding and catalytic domains. These findings provide a strong computational foundation for experimental validation and suggest that safe, natural compounds—especially polyphenols—can serve as promising multitarget therapeutics against BoNT/A toxicity.