Abstract
Helicobacter pylori (H. pylori) is a pathogen that can remain in the stomach of an infected person for their entire life. As a result, this leads to the development of severe gastric diseases such as gastric cancer. In addition, current therapies have several problems including antibiotics resistance. Therefore, new practical options to eliminate this bacterium, and its induced affections, are required to avoid morbidity and mortality worldwide. One strategy in the search for new drugs is to detect compounds that inhibit a limiting step in a central metabolic pathway of the pathogen of interest. In this work, we tested 55 compounds to gain insights into their possible use as new inhibitory drugs of H. pylori glucose-6-phosphate dehydrogenase (HpG6PD) activity. The compounds YGC-1; MGD-1, MGD-2; TDA-1; and JMM-3 with their respective scaffold 1,3-thiazolidine-2,4-dione; 1H-benzimidazole; 1,3-benzoxazole, morpholine, and biphenylcarbonitrile showed the best inhibitory activity (IC50 = 310, 465, 340, 204 and 304 μM, respectively). We then modeled the HpG6PD protein by homology modeling to conduct an in silico study of the chemical compounds and discovers its possible interactions with the HpG6PD enzyme. We found that compounds can be internalized at the NADP+ catalytic binding site. Hence, they probably exert a competitive inhibitory effect with NADP+ and a non-competitive or uncompetitive effect with G6P, that of the compounds binding far from the enzyme’s active site. Based on these findings, the tested compounds inhibiting HpG6PD represent promising novel drug candidates against H. pylori.
Highlights
Helicobacter pylori (H. pylori) is a Gram-negative bacterium that infects approximately50% of the world’s population
The results showed that compounds of H. pylori without the homo sapiens G6PD (HsG6PD)
Josue Martínez-Miranda (JMM)-3, the most stable protein–ligand complex, showed a ∆G = −8.55 kcal/moll. These results revealed that the Yelzyn Galván-Ciprés (YGC)-1, YGC-3, MGD1, MGD-2, Thalia Delgado-Aguilar (TDA)-1, and JMM-3 probably affect the correct binding of catalytic NADP+
Summary
It colonizes the human stomach, causing a broad spectrum of diseases ranging from gastritis and gastric ulcers to stomach cancer [1,2], the latter being the third leading cause of cancer death worldwide—with 90% of cases being related to. H. pylori infection [3]. The effective and efficient eradication of H. pylori infection could reduce its enormous negative consequences in humans. There are no exclusive drugs against H. pylori, and current treatments consist of combining two or three antibiotics (clarithromycin, amoxicillin, and metronidazole) with one proton pump inhibitor such as omeprazole [5,6]. The finding of H. pylori strains that are resistant to clarithromycin or metronidazole compromises these therapeutic strategies [7]
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