{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T21:13:38Z","timestamp":1789766018558,"version":"4.0.1"},"reference-count":59,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ANID FONDECYT de Iniciaci\u00f3n","award":["11220444"],"award-info":[{"award-number":["11220444"]}]},{"name":"ANID FONDECYT de Iniciaci\u00f3n","award":["FOVI230136"],"award-info":[{"award-number":["FOVI230136"]}]},{"name":"ANID FONDECYT Regular","award":["1241305"],"award-info":[{"award-number":["1241305"]}]},{"name":"ANID FONDECYT Regular","award":["1250346"],"award-info":[{"award-number":["1250346"]}]},{"name":"ANID FONDECYT de Iniciaci\u00f3n","award":["11230033"],"award-info":[{"award-number":["11230033"]}]},{"name":"FONDECYT project","award":["1251871"],"award-info":[{"award-number":["1251871"]}]},{"name":"ANID FONDECYT de Iniciaci\u00f3n","award":["11241091"],"award-info":[{"award-number":["11241091"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Helicobacter pylori urease (HpU) plays a central role in bacterial survival and virulence by hydrolyzing urea into ammonia and carbon dioxide, neutralizing gastric acidity, and facilitating host colonization. The increasing prevalence of antibiotic resistance underscores the need for alternative strategies targeting essential bacterial enzymes such as urease. In this study, a multistage computational pipeline integrating pharmacophore modeling, machine learning (ML), ensemble docking, and enhanced molecular dynamics simulations were applied to identify novel triazole-based HpU inhibitors. Starting from over seven million compounds in the ZINC15 database, pharmacophore- and ML-based filters progressively reduced the chemical space to 7062 candidates. Ensemble docking across 25 conformational frames of HpU, followed by quantum-polarized ligand docking (QPLD), identified seven promising ligands exhibiting strong binding energies and stable metal coordination. Molecular dynamics (MD) simulations under progressively relaxed restraints revealed three highly stable complexes (CA1, CA3, and CA6). Subsequent well-tempered metadynamics (WT-MetaD) simulations reconstructed free-energy landscapes showing deep, localized basins for CA3 and CA6, comparable to the potent reference inhibitor DJM, supporting their potential as strong urease binders. Finally, unsupervised chemical space mapping using the UMAP algorithm positioned these candidates within molecular regions associated with potent urease inhibitors, further validating their structural coherence and pharmacophoric relevance. An ADMET assessment confirmed that the selected candidates exhibit physicochemical and early safety properties compatible with subsequent in vitro evaluation. This multilevel screening strategy demonstrates the power of combining ML-driven classification, ensemble docking, and enhanced sampling simulations to discover non-hydroxamic urease inhibitors. Although the current findings are computational, they provide a rational foundation for future in vitro validation and for expanding the discovery of triazole-based scaffolds targeting ureolytic enzymes.<\/jats:p>","DOI":"10.3390\/ijms262311576","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T08:13:49Z","timestamp":1764576829000},"page":"11576","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Integrative Computational Approaches for the Discovery of Triazole-Based Urease Inhibitors: A Machine Learning, Virtual Screening, and Meta-Dynamics Framework"],"prefix":"10.3390","volume":"26","author":[{"given":"Sof\u00eda E.","family":"R\u00edos-Rozas","sequence":"first","affiliation":[{"name":"Laboratorio de Bioinform\u00e1tica y Qu\u00edmica Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Cat\u00f3lica del Maule, Talca 3480094, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Morales","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioinform\u00e1tica y Qu\u00edmica Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Cat\u00f3lica del Maule, Talca 3480094, Chile"},{"name":"Doctorado en Ingenier\u00eda, Facultad de Ingenier\u00eda, Universidad Cat\u00f3lica del Maule, Talca 3480094, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Vald\u00e9s-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioinform\u00e1tica y Qu\u00edmica Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Cat\u00f3lica del Maule, Talca 3480094, Chile"},{"name":"Doctorado en Biotecnolog\u00eda Traslacional, Facultad de Ciencias Agrarias y Forestales, Universidad Cat\u00f3lica del Maule, Talca 3480094, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3871-0261","authenticated-orcid":false,"given":"Gabriela","family":"Urra","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioinform\u00e1tica y Qu\u00edmica Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Cat\u00f3lica del Maule, Talca 3480094, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila A.","family":"Flores-Morales","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioinform\u00e1tica y Qu\u00edmica Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Cat\u00f3lica del Maule, Talca 3480094, Chile"},{"name":"Doctorado en Ingenier\u00eda, Facultad de Ingenier\u00eda, Universidad Cat\u00f3lica del Maule, Talca 3480094, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1828-4656","authenticated-orcid":false,"given":"Javier","family":"Far\u00edas-Abarca","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioinform\u00e1tica y Qu\u00edmica Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Cat\u00f3lica del Maule, Talca 3480094, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erix W.","family":"Hern\u00e1ndez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioinform\u00e1tica y Qu\u00edmica Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Cat\u00f3lica del Maule, Talca 3480094, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3924-1907","authenticated-orcid":false,"given":"Jonathan M.","family":"Palma","sequence":"additional","affiliation":[{"name":"Facultad de Ingenier\u00eda, Universidad de Talca, Maule, Curic\u00f3 3349001, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1297-8351","authenticated-orcid":false,"given":"Manuel I.","family":"Osorio","sequence":"additional","affiliation":[{"name":"Facultad de Odontolog\u00eda, Universidad Andr\u00e9s Bello, Santiago Chile, Echaurren 237, Santiago 8370133, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8993-9353","authenticated-orcid":false,"given":"Osvaldo","family":"Y\u00e1\u00f1ez-Osses","sequence":"additional","affiliation":[{"name":"Centro de Modelaci\u00f3n Ambiental y Din\u00e1mica de Sistemas (CEMADIS), Facultad de Ingenier\u00eda y Negocios, Universidad de Las Am\u00e9ricas, Santiago 7500975, 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