Integrated In Silico Analysis Reveals ABC Transporter ATP-Binding Protein as a Therapeutic Target in Helicobacter pylori

Abstract Helicobacter pylori remains a major cause of gastric diseases, while increasing antimicrobial resistance highlights the need for novel therapeutic targets. Here, we developed a comprehensive computational target-prioritization framework integrating Rosetta Stone domain-fusion analysis, subtractive genomics, metabolic pathway mapping, structural modeling, and molecular dynamics simulations to identify pathogen-specific drug targets in H. pylori J99. Twelve conserved domain families comprising 746 proteins were identified, and domain abundance showed a weak negative correlation with versatility (r = −0.327), suggesting functional specialization through domain expansion. Sequential filtering based on essentiality, nonhomology to the human proteome and gut microbiota, subcellular localization, and druggability prioritized five candidate proteins, with the ATP-binding protein AAD06727.1 emerging as the most promising target. AlphaFold2 modeling produced a high-confidence structure containing a conserved nucleotide-binding pocket. Molecular docking identified 5′-fluorosulfonylbenzoyl-5′-adenosine (FSBA) as the highest-affinity ligand (−7.3 kcal mol–1), outperforming ATP and verapamil. Triplicate 1 μs molecular dynamics simulations of apo and halo AAD06727.1 demonstrated stable rmsd, RMSF, radius of gyration, solvent-accessible surface area, hydrogen-bond occupancy, and principal component profiles, indicating preservation of structural integrity following ATP binding. Comparative simulations with the human ABCA12 nucleotide-binding domain showed conserved global architecture while revealing distinct ligand-recognition characteristics. Together, these findings identify AAD06727.1 as a structurally stable, pathogen-specific ATP-binding protein that represents a promising candidate for future structure-guided anti-H. pylori drug development.