Computational-driven discovery of AI-2 quorum sensing inhibitor targeting the 5′- methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) to combat drug-resistant Helicobacter pylori

MTAN is an attainable therapeutic target for H. pylori because it may minimize virulence production, limit resistance, and impair quorum sensing without affecting gut flora. Here, 457 compounds with anti-H. pylori activity were methodically analyzed, revealing a diverse array of chemical classes and unique compounds. Molecular docking studies identified three potential compounds with high binding affinities, Dehydrocostus lactone, keramamine B, and ZINC00013531409, each having binding affinity of −7.9, −9.2, and −8.3 kcal/mol, respectively. Molecular dynamics simulations of the ZINC00013531409-MTAN interactions in comparison with Apo-MTAN demonstrated stability and interactions of 300 ns, with key residues involved in protein-ligand binding illuminated. Analysis of hydrogen bonds (Ile52, Met174, and Arg194) and secondary structure variations further elucidated the binding interactions and conformational changes within the complex. Binding free energy calculations shed light on the energetics and interactions governing the complex formation of the ZINC00013531409-MTAN complex. PCA elucidated the dominant modes of motion, along with FEL revealed the energetically favorable states and then DCCM shed light on the correlated motions between residues. Overall, this study offers a detailed computational evaluation of ZINC00013531409 with anti-H. pylori activity, highlighting toxicity profile, conformational stability, and binding interactions, providing a foundation for further drug development efforts toward bacterial resistance.