Docking-Guided Identification of Natural Urease Inhibitors Against Helicobacter pylori: Integrated ADME, Molecular Dynamics, and DFT Investigations
Abstract
Helicobacter pylori is a Gram-negative, microaerophilic bacterium implicated in the development of chronic gastritis, peptic ulcer disease, gastric adenocarcinoma, and MALT lymphoma. The increasing frequency of resistance to antibiotic and treatment failures related with conventional therapies has created an urgent need for the novel discovery of an anti-H. pylori agents. Urease, a key virulence factor responsible for bacterial survival in the acidic gastric environment, represents an attractive molecular target for therapeutic intervention. The present study aimed to identify potential natural urease inhibitors through a docking-guided screening approach. A total of 126 phytoconstituents from medicinal plants possessing anti-H. pylori activity were selected and subjected to in silico evaluation. Of the screened compounds, 92 satisfied the selected drug-likeness criteria and were subsequently investigated through molecular docking against H. pylori urease. Docking analysis identified several compounds with notable binding affinity toward urease. Among them, sphaeranthanolide exhibited the highest binding interaction (-7.6 kcal/mol), followed by (+)-catechin (-7.5 kcal/mol), scopoline, epicatechin, and (+)-hardwickiic acid (-7.4 kcal/mol). Detailed interaction analysis revealed the involvement of key active-site residues, including Asp362, Arg338, Gly279, Ala169, Glu222, His221, and Asp223, through hydrogen bonding and hydrophobic interactions. Based on its superior docking results, sphaeranthanolide was selected for further MD simulation and DFT calculations studies. A 100 ns MD simulation confirmed the structural stability of the sphaeranthanolide-urease complex, with persistent interactions maintained throughout the simulation period. DFT calculations demonstrated favorable electronic characteristics, with HOMO and LUMO energies of -11.018 eV and -7.130 eV, respectively, and a HOMO-LUMO energy gap of 3.888 eV. Overall, the integrated application of ADME prediction, molecular docking, MD simulation, and DFT analysis identified sphaeranthanolide as a promising urease inhibitor and lead potential molecule for the development of novel anti-H. pylori agents. The significance findings provide a scientific basis for future experimental validation and further optimization of natural product-derived urease inhibitors.
Keywords:
Helicobacter pylori, Urease Inhibitors, Natural Products, ADME Prediction, Molecular Docking, SphaeranthanolideDOI
https://doi.org/10.25004/IJPSDR.2026.180403References
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