Computational Study of Amino Acid-Transition Metal Complexes as potential Helicobacter pylori Urease Enzyme Inhibitors: DFT, Molecular Docking and ADMET analysis

Helicobacter pylori infection, driven by urease enzyme activity, demands new inhibitors with balanced efficacy and safety. In this study, a computational investigation was conducted to evaluate the inhibitory potential of selected amino acids (serine, valine, and histidine) and their transition metal complexes against H. pylori urease. The molecular structures of the ligands and their Cu(II), Ni(II), and Zn(II) complexes were optimized using density functional theory (DFT) at the B3LYP level. Molecular docking simulations were subsequently performed to examine the binding affinity and interaction patterns of the compounds within the urease active site. Docking validation yielded a root-mean-square deviation (RMSD) of 1.5 Å, confirming the reliability of the docking protocol. The docking results showed that metal coordination significantly improved binding affinity compared with the free amino acids. Among the investigated compounds, Cu(histidine) exhibited the strongest interaction with the enzyme with a docking score of −116.28, followed by Zn(histidine) (−110.91) and Ni(histidine) (−108.74). Drug-likeness and pharmacokinetic evaluation using SwissADME indicated favourable physicochemical properties and acceptable absorption characteristics, while Toxicity profiling revealed excellent safety for free amino acids (LD₅₀: 12,680–15,000 mg/kg; class 6), while complexes demonstrated moderate toxicity (LD₅₀: 320–5500 mg/kg; classes 4–5). The complexes consistently flagged nephrotoxicity as active, with certain species also showing borderline carcinogenic and immunotoxic potentials. Frontier molecular orbital analysis further indicated that metal complexation reduced the HOMO–LUMO energy gap, suggesting enhanced chemical reactivity and improved interaction potential with the urease active site. Overall, histidine-based metal complexes may represent promising scaffolds for the development of novel H. pylori urease inhibitors.