Unveiling Novel Urease Inhibitors for <i>Helicobacter pylori</i>: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations

Unveiling Novel Urease Inhibitors for <i>Helicobacter pylori</i>: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations

<i>Helicobacter pylori</i> (<i>Hp</i>) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key <i>Hp</i> virulence factor hydrolyzes urea, facilitating bacterial survival in the acidic gastric...

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Bibliographic Details
Main Authors:	Paulina Valenzuela-Hormazabal, Romina V. Sepúlveda, Melissa Alegría-Arcos, Elizabeth Valdés-Muñoz, Víctor Rojas-Pérez, Ileana González-Bonet, Reynier Suardíaz, Christian Galarza, Natalia Morales, Verónica Leddermann, Ricardo I. Castro, Bruna Benso, Gabriela Urra, Erix W. Hernández-Rodríguez, Daniel Bustos
Format:	Article
Language:	English
Published:	MDPI AG 2024-02-01
Series:	International Journal of Molecular Sciences
Subjects:	computer-aided drug design structure-based virtual screening pharmacophore-based virtual screening molecular dynamics simulations ADMET urease
Online Access:	https://www.mdpi.com/1422-0067/25/4/1968

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Summary:	<i>Helicobacter pylori</i> (<i>Hp</i>) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key <i>Hp</i> 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 <i>Hp</i> urease (<i>Hp</i>U). 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 <i>Hp</i>U inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.
ISSN:	1661-6596 1422-0067