Biophysical and computational insights on the stability and molecular interactions of <i>Helicobacter pylori</i> 5′-methylthioadenosine/ <i>S</i> -adenosyl homocysteine nucleosidase MTAN with benzimidazole derivatives

Helicobacter pylori is a Gram-negative bacterium that colonizes the stomach lining of more than half the global population. H. pylori infection is strongly associated with an increased risk of stomach cancer, making it a critical target for gastrointestinal disease research. The widespread use of various drugs has led to the development of antibiotic resistance. This growing resistance highlights the urgent need for more effective therapies. 5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a crucial enzyme in H. pylori, playing a key role in quorum sensing, menaquinone biosynthesis, and the recycling of adenosine-based metabolites. It also catalyzes the hydrolysis of the N-ribosidic bond in S-adenosylhomocysteine (SAH) and 5′-MTA, facilitating essential metabolic pathways. Targeting this enzyme could impair bacterial metabolism, which leads to the development of antibiotics without disrupting gut microbiota. Here, differential scanning fluorimetry (DSF) and circular dichroism (CD) spectroscopy were used to evaluate the stability and structural alterations of MTAN upon binding with benzimidazole derivatives, complemented by in silico docking studies. The findings indicate that benzimidazole derivatives may serve as potential MTAN inhibitors, with compounds 20, 23, and 31 showing the most notable effect on the enzyme’s stability. These findings lay the groundwork for designing novel MTAN inhibitors with therapeutic potential against H. pylori infections.