Dynamics based screening of Therapeutic compounds against Helicobacter pylori targeting TNF-α inducing protein

In about half of the world's population, Helicobacter pylori (H. pylori) is the cause of stomach ulcers. 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 Tumour Necrosis Factor-alpha Inducing Protein (Tip-α) is important in the development of gastric cancer, especially in patients with chronic ulcers. Because of its vital role, Tip-α may be a good target for medication. Using molecular docking experiments, two different binding sites on Tip-α were found, and possible inhibitors were assessed. ZINC11981988 and ZINC04243820, two ZINC database hits among the screened compounds, showed a significant binding affinity to Tip-α, with glide scores of -9.116 kcal/mol and -10.455 kcal/mol, respectively. A MM-GBSA analysis was conducted to have a better understanding of their binding mechanisms. The findings showed that the selectivity of Tip-α inhibitors was more influenced by electrostatic energy contributions than by van der Waals interactions. The stability of these ligands in their respective binding sites was evaluated using molecular dynamics (MD) simulations upto 100 ns. In contrast to ZINC11981988, ZINC04243820 showed a more stable binding association with Tip-α, according to the MD analysis. According to this, ZINC04243820 exhibits excellent binding stability and is therefore a promising candidate for additional research. Considering these results, ZINC04243820 could be proposed as potential lead to construct Tip-α inhibitors against H. pylori which shows favourable interaction properties and persistent binding. Further, in vivo and in vitro investigations are required to examine and validate its therapeutic potential.