Unveiling novel urease inhibitors for Helicobacter pylori: A multi-methodological approach from virtual screening and ADME to molecular dynamics simulations

dc.creatorValenzuela-Hormazabal, Paulina
dc.creatorSepúlveda, Romina V.
dc.creatorAlegría-Arcos, Melissa
dc.creatorValdés-Muñoz, Elizabeth
dc.creatorRojas-Pérez, Víctor
dc.creatorGonzález-Bonet, Ileana
dc.creatorSuardíaz, Reynier
dc.creatorGalarza, Christian
dc.creatorMorales, Natalia
dc.creatorLeddermann, Verónica
dc.creatorCastro, Ricardo I.
dc.creatorBenso, Bruna
dc.creatorUrra, Gabriela
dc.creatorHernández-Rodríguez, Erix W.
dc.creatorBustos, Daniel
dc.date2024-04-16T19:17:28Z
dc.date2024-04-16T19:17:28Z
dc.date2024
dc.date.accessioned2024-05-02T20:32:25Z
dc.date.available2024-05-02T20:32:25Z
dc.identifierhttp://repositorio.ucm.cl/handle/ucm/5310
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/9275491
dc.descriptionHelicobacter pylori (Hp) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key Hp virulence factor hydrolyzes urea, facilitating bacterial survival in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for Hp urease (HpU). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel HpU inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.
dc.languageen
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 Chile
dc.rightshttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/
dc.sourceInternational Journal of Molecular Sciences, 25(4),1968
dc.subjectComputer-aided drug design
dc.subjectStructure-based virtual screening
dc.subjectPharmacophore-based virtual screening
dc.subjectMolecular dynamics simulations
dc.subjectADMET
dc.subjectUrease
dc.subjectHelicobacter pylori
dc.titleUnveiling novel urease inhibitors for Helicobacter pylori: A multi-methodological approach from virtual screening and ADME to molecular dynamics simulations
dc.typeArticle


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