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

Author:

Valenzuela-Hormazabal Paulina1ORCID,Sepúlveda Romina V.2ORCID,Alegría-Arcos Melissa3,Valdés-Muñoz Elizabeth4,Rojas-Pérez Víctor4,González-Bonet Ileana5,Suardíaz Reynier6ORCID,Galarza Christian7ORCID,Morales Natalia8,Leddermann Verónica8,Castro Ricardo I.9,Benso Bruna10ORCID,Urra Gabriela11,Hernández-Rodríguez Erix W.1112ORCID,Bustos Daniel11ORCID

Affiliation:

1. Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción 4030000, Chile

2. Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andres Bello, Av. República 330, Santiago 8370146, Chile

3. Núcleo de Investigación en Data Science, Facultad de Ingeniería y Negocios, Universidad de las Américas, Santiago 7500000, Chile

4. Doctorado en Biotecnología Traslacional, Facultad de Ciencias Agrarias y Forestales, Universidad Católica del Maule, Talca 3480094, Chile

5. Biomedical Research Labs, Facultad de Medicina, Universidad Católica del Maule, Talca 3480094, Chile

6. Departamento de Química Física, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid, Spain

7. Departamento de Matemáticas, Facultad de Ciencias Naturales y Matemáticas, Escuela Superior Politécnica del Litoral, Guayaquil 090112, Ecuador

8. Magíster en Ciencias de la Computación, Universidad Católica del Maule, Talca 3460000, Chile

9. Multidisciplinary Agroindustry Research Laboratory, Instituto de Ciencias Aplicadas, Facultad de Arquitectura, Construcción y Medio Ambiente, Universidad Autónoma de Chile, Cinco Pte. N°1670, Talca 3467987, Chile

10. School of Dentistry, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 7810000, Chile

11. Laboratorio de Bioinformática y Química Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Católica del Maule, Talca 3480094, Chile

12. Unidad de Bioinformática Clínica, Centro Oncológico, Facultad de Medicina, Universidad Católica del Maule, Talca 3480094, Chile

Abstract

Helicobacter 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.

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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