Screening of putative inhibitors for cytotoxin VacA from Helicobacter pylori

Cytotoxin VacA, a major virulence factor of Helicobacter pylori-the principal etiological agent of gastric cancer-represents a compelling therapeutic target. Pharmacological inhibition of VacA through small-molecule agents offers a putative strategy to substantially mitigate gastric carcinogenesis risk. Notably, contemporary medical practice lacks a single "specific drug" capable of independently eradicating H. pylori, with current management limited to anti-inflammatory regimens. In this context, drug repurposing has gained prominence as a cost-efficient paradigm in pharmaceutical innovation, optimizing resource allocation during the discovery phase. The present investigation thus focuses on identifying novel small-molecule inhibitors specifically targeting the VacA protein. Our multi-tiered screening methodology integrates computational and biophysical approaches: molecular docking, ADMET, Molecular Dynamics (MD) simulations and MM/PBSA calculations with the ZINC15 database constituting our primary compound source.Following rigorous virtual screening, seven lead candidates emerged based on AutoDock Vina scoring metrics. These were subjected to extended molecular dynamics simulations to validate binding affinity and conformational resilience under physiological conditions. Subsequent pharmacokinetic profiling benchmarked key parameters against established drug-likeness criteria, while energy decomposition analysis precisely mapped critical protein-ligand interaction hotspots within the VacA binding pocket. This systematic investigation not only identifies putative small-molecule inhibitors of cytotoxin VacA but also delineates a rational framework for virulence factor-targeted therapy against H. pylori infection. Our approach establishes a blueprint for next-generation antimicrobials that could transform the therapeutic landscape of gastric cancer prevention through targeted virulence attenuation.