Dynamics-Driven Screening of Inhibitors Targeting TNF-α Inducing Protein to Mitigate Infection of <i>Helicobacter pylori</i>

Helicobacter pylori(H. pylori) is responsible for stomach ulcers in approximately half of the global population. Due to the extensive use of different drugs to treat H. pylori infections, multidrug resistance has developed, making treatment more difficult. Finding a viable therapeutic target becomes increasingly important as antibiotic resistance keeps increasing. A distinct protein of H. pylori called Tumor Necrosis Factor-alpha Inducing Protein (Tip-[Formula: see text] is important in the development of gastric cancer, especially in patients with chronic ulcers; therefore, Tip-[Formula: see text] is considered an effective target. Using molecular docking experiments, two different binding sites on Tip-[Formula: see text] were found, and possible inhibitors were assessed. Among the screened compounds from the ZINC database, Anti-Tip1 and Anti-Tip6 emerged as potential candidates, exhibiting notable binding affinity toward the Tip-[Formula: see text] protein. Their respective QPLD and IFD scores of −9.116 kcal/mol and −10.455 kcal/mol indicate strong molecular interactions, suggesting their potential as effective inhibitors. A MM-GBSA analysis was conducted to have a better understanding of their binding mechanisms. The findings showed that the selectivity of Tip-[Formula: see text] inhibitors was more influenced by electrostatic energy contributions than by van der Waals interactions. The significant stability of these ligands in their respective binding sites was observed using molecular dynamics (MD) simulations up to 100 ns, and therefore could be proposed as potential leads to construct Tip-[Formula: see text] inhibitors against H. pylori. Further, in vivo and in vitro investigations are required to examine and validate its therapeutic potential.