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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| Format: | Article |
| Language: | English |
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MDPI AG
2024-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/4/1968 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Paulina Valenzuela-Hormazabal |
| collection | DOAJ |
| description | <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. |
| first_indexed | 2024-03-07T22:29:46Z |
| format | Article |
| id | doaj.art-7e05afd178a648809ebbfdbdf94badcf |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-07T22:29:46Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7e05afd178a648809ebbfdbdf94badcf2024-02-23T15:19:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-02-01254196810.3390/ijms25041968Unveiling Novel Urease Inhibitors for <i>Helicobacter pylori</i>: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics SimulationsPaulina Valenzuela-Hormazabal0Romina V. Sepúlveda1Melissa Alegría-Arcos2Elizabeth Valdés-Muñoz3Víctor Rojas-Pérez4Ileana González-Bonet5Reynier Suardíaz6Christian Galarza7Natalia Morales8Verónica Leddermann9Ricardo I. Castro10Bruna Benso11Gabriela Urra12Erix W. Hernández-Rodríguez13Daniel Bustos14Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción 4030000, ChileCenter for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andres Bello, Av. República 330, Santiago 8370146, ChileNúcleo de Investigación en Data Science, Facultad de Ingeniería y Negocios, Universidad de las Américas, Santiago 7500000, ChileDoctorado en Biotecnología Traslacional, Facultad de Ciencias Agrarias y Forestales, Universidad Católica del Maule, Talca 3480094, ChileDoctorado en Biotecnología Traslacional, Facultad de Ciencias Agrarias y Forestales, Universidad Católica del Maule, Talca 3480094, ChileBiomedical Research Labs, Facultad de Medicina, Universidad Católica del Maule, Talca 3480094, ChileDepartamento de Química Física, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid, SpainDepartamento de Matemáticas, Facultad de Ciencias Naturales y Matemáticas, Escuela Superior Politécnica del Litoral, Guayaquil 090112, EcuadorMagíster en Ciencias de la Computación, Universidad Católica del Maule, Talca 3460000, ChileMagíster en Ciencias de la Computación, Universidad Católica del Maule, Talca 3460000, ChileMultidisciplinary Agroindustry Research Laboratory, Instituto de Ciencias Aplicadas, Facultad de Arquitectura, Construcción y Medio Ambiente, Universidad Autónoma de Chile, Cinco Pte. N°1670, Talca 3467987, ChileSchool of Dentistry, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 7810000, ChileLaboratorio de Bioinformática y Química Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Católica del Maule, Talca 3480094, ChileLaboratorio de Bioinformática y Química Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Católica del Maule, Talca 3480094, ChileLaboratorio de Bioinformática y Química Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Católica del Maule, Talca 3480094, Chile<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.https://www.mdpi.com/1422-0067/25/4/1968computer-aided drug designstructure-based virtual screeningpharmacophore-based virtual screeningmolecular dynamics simulationsADMETurease |
| spellingShingle | 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 Unveiling Novel Urease Inhibitors for <i>Helicobacter pylori</i>: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations International Journal of Molecular Sciences computer-aided drug design structure-based virtual screening pharmacophore-based virtual screening molecular dynamics simulations ADMET urease |
| title | Unveiling Novel Urease Inhibitors for <i>Helicobacter pylori</i>: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations |
| title_full | Unveiling Novel Urease Inhibitors for <i>Helicobacter pylori</i>: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations |
| title_fullStr | Unveiling Novel Urease Inhibitors for <i>Helicobacter pylori</i>: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations |
| title_full_unstemmed | Unveiling Novel Urease Inhibitors for <i>Helicobacter pylori</i>: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations |
| title_short | Unveiling Novel Urease Inhibitors for <i>Helicobacter pylori</i>: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations |
| title_sort | unveiling novel urease inhibitors for i helicobacter pylori i a multi methodological approach from virtual screening and adme to molecular dynamics simulations |
| topic | computer-aided drug design structure-based virtual screening pharmacophore-based virtual screening molecular dynamics simulations ADMET urease |
| url | https://www.mdpi.com/1422-0067/25/4/1968 |
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