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<p><i>Helicobacter pylori</i> urease is a nickel-dependent metalloenzyme that plays a critical role in bacterial survival and colonization within the acidic gastric environment, making it an attractive therapeutic target. In this study, the inhibitory potential of selected amino acids (serine, valine, and histidine) and their Cu(II), Ni(II), and Zn(II) complexes against <i>H. pylori</i> urease was investigated using density functional theory (DFT), molecular docking, drug-likeness evaluation, ADMET prediction, and toxicity assessment. Histidine was selected because of its metal-binding imidazole side chain, while serine and valine were chosen as representative amino acids possessing distinct coordination and physicochemical properties. Copper, nickel, and zinc were investigated due to their biological relevance and ability to modulate ligand–enzyme interactions through metal complexation. Molecular docking results revealed that metal coordination significantly enhanced binding affinity relative to the free amino acids. Among all investigated compounds, Cu(his)₂ exhibited the most favourable MolDock score (− 116.28&#xa0;kcal/mol), followed by Zn(his)₂ (− 110.91&#xa0;kcal/mol) and Ni(his)₂ (− 108.74&#xa0;kcal/mol), with extensive hydrogen-bonding and hydrophobic interactions observed within the urease active site. Drug-likeness analysis indicated that all compounds satisfied Lipinski’s Rule of Five without violations and possessed acceptable bioavailability characteristics. ADMET predictions suggested favourable metabolic profiles with minimal cytochrome P450 inhibition, while toxicity assessment indicated low toxicity for the free amino acids and moderate toxicity for several metal complexes, particularly copper-containing derivatives. Frontier molecular orbital analysis further demonstrated that metal complexation altered electronic properties and generally enhanced molecular reactivity. These computational findings suggest that histidine-based transition-metal complexes, particularly Cu(his)₂, warrant further investigation as potential urease-targeting agents. However, experimental validation through in vitro and in vivo studies is required to confirm their efficacy and safety.</p> Graphical Abstract <p></p>

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Computational study of amino acid-transition metal complexes as potential Helicobacter pylori urease enzyme inhibitors: DFT, molecular docking and ADMET analysis

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  • 发表日期：

    2026年7月21日

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  • Muhammad Mustapha Abdullahi,
  • Safiya Abdulsalam,
  • Sa’adatu Auwal Hamza,
  • Madina Imam

摘要

Helicobacter pylori urease is a nickel-dependent metalloenzyme that plays a critical role in bacterial survival and colonization within the acidic gastric environment, making it an attractive therapeutic target. In this study, the inhibitory potential of selected amino acids (serine, valine, and histidine) and their Cu(II), Ni(II), and Zn(II) complexes against H. pylori urease was investigated using density functional theory (DFT), molecular docking, drug-likeness evaluation, ADMET prediction, and toxicity assessment. Histidine was selected because of its metal-binding imidazole side chain, while serine and valine were chosen as representative amino acids possessing distinct coordination and physicochemical properties. Copper, nickel, and zinc were investigated due to their biological relevance and ability to modulate ligand–enzyme interactions through metal complexation. Molecular docking results revealed that metal coordination significantly enhanced binding affinity relative to the free amino acids. Among all investigated compounds, Cu(his)₂ exhibited the most favourable MolDock score (− 116.28 kcal/mol), followed by Zn(his)₂ (− 110.91 kcal/mol) and Ni(his)₂ (− 108.74 kcal/mol), with extensive hydrogen-bonding and hydrophobic interactions observed within the urease active site. Drug-likeness analysis indicated that all compounds satisfied Lipinski’s Rule of Five without violations and possessed acceptable bioavailability characteristics. ADMET predictions suggested favourable metabolic profiles with minimal cytochrome P450 inhibition, while toxicity assessment indicated low toxicity for the free amino acids and moderate toxicity for several metal complexes, particularly copper-containing derivatives. Frontier molecular orbital analysis further demonstrated that metal complexation altered electronic properties and generally enhanced molecular reactivity. These computational findings suggest that histidine-based transition-metal complexes, particularly Cu(his)₂, warrant further investigation as potential urease-targeting agents. However, experimental validation through in vitro and in vivo studies is required to confirm their efficacy and safety.

Graphical Abstract