{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T14:07:03Z","timestamp":1793369223930,"version":"4.5.0"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Various human diseases including gastric inflammation, ulcers, stomach malignancies, and even coronary heart disease are significantly influenced by the infection of the gram-negative bacterium\n                    <jats:italic>Helicobacter pylori.<\/jats:italic>\n                    While antibiotics are commonly used to treat\n                    <jats:italic>H. pylori<\/jats:italic>\n                    infection, their effectiveness is compromised by the development of antibiotic resistance. Therefore, the development of novel therapeutics against this pathogen is imperative. The virulence factor \u201cvacuolating cytotoxin autotransporter (VacA)\u201d was annotated from\n                    <jats:italic>H. pylori<\/jats:italic>\n                    genome by using the RAST server. All strains of\n                    <jats:italic>H. pylori<\/jats:italic>\n                    contain VacA toxin. Phyre2 and SWISS-MODEL servers were used for modeling and evaluating the structure of the active site containing p55 domain of VacA toxin (PDB: 2QV3) which shows the Ramachandran plot (98.68%), MolProbity Score (1.32), Bad Bonds (0), and Clash Score (5.78) of the refined model of VacA toxin. Autodock Vina was used to dock 3000 ligand molecules obtained from the ZINC15 database which identified only 178 ligands bind to VacA\u2019s active site. Molecular docking and ADMET studies predicted ZINC4004291 ((3As,4R,9bS)-4-pyridin-4-yl-8-(trifluoromethyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolone) as the best inhibitor of VacA toxin based on its strong binding affinity (\u22126.9 kcal\/mol) and low toxicity. Molecular dynamics simulation indicated favourable levels of RMSD, RMSF, Rg, SASA and Hbonds exploring the stable dynamics of the docking complex between the p55 domain of VacA toxin and ZINC4004291 ligand. Moreover, principal component analysis and Gibbs free energy landscape studies indicate the favourable thermodynamic stability of the complex during 100 ns simulation period. Thus, the ligand ZINC4004291 is a computationally identified in silico hit for a possible drug to treat\n                    <jats:italic>H. pylori<\/jats:italic>\n                    infection, while additional experimental validation required.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0354383","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T17:41:52Z","timestamp":1784742112000},"page":"e0354383","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Structure-guided identification of a potential inhibitor targeting the VacA toxin of Helicobacter pylori"],"prefix":"10.1371","volume":"21","author":[{"given":"Farzana","family":"Akter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md. 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BIOVIA","year":"2017"},{"issue":"9","key":"pone.0354383.ref036","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures","volume":"58","author":"DEV Pires","year":"2015","journal-title":"J Med Chem"},{"key":"pone.0354383.ref037","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"A Daina","year":"2017","journal-title":"Sci Rep"},{"issue":"10","key":"pone.0354383.ref038","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1002\/jcc.21787","article-title":"MDAnalysis: a toolkit for the analysis of molecular dynamics simulations","volume":"32","author":"N Michaud-Agrawal","year":"2011","journal-title":"J Comput 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Farmer","year":"2017","journal-title":"Entropy (Basel)"},{"issue":"6","key":"pone.0354383.ref045","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1080\/07391102.2013.795871","article-title":"Genome-based approaches to develop epitope-driven subunit vaccines against pathogens of infective endocarditis","volume":"32","author":"V Priyadarshini","year":"2014","journal-title":"J Biomol Struct Dyn"},{"issue":"2","key":"pone.0354383.ref046","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1093\/bib\/bbaa382","article-title":"Exploration of natural compounds with anti-SARS-CoV-2 activity via inhibition of SARS-CoV-2 Mpro","volume":"22","author":"S Bharadwaj","year":"2021","journal-title":"Brief Bioinform"},{"issue":"3","key":"pone.0354383.ref047","doi-asserted-by":"crossref","first-page":"100523","DOI":"10.1016\/j.jgeb.2025.100523","article-title":"Designing siRNAs against non-structural genes of all serotypes of Dengue virus using RNAi technology - A computational 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