Utilizing the drug repurposing strategy on current drugs: new leads for peptic ulcers via biochemical and biomolecular dynamics studies

Abstract

The hyperactivity of urease enzymes plays a crucial role in the development of hepatic coma, hepatic encephalopathy, urolithiasis, gastric and peptic ulcers. Additionally, these enzymes adversely impact the soil’s nitrogen efficiency for crop production. In the current study 100 known drugs were tested against Jack Bean urease and Proteus mirabilis urease and identified three inhibitors i.e. terbutaline (compound 1), Ketoprofen (compound 2) and norepinephrine bitartrate (compound 3). As a result, these compounds showed excellent inhibition against Jack Bean urease i.e. (IC₅₀ = 2.1–11.3 µM), and Proteus mirabilis urease (4.8–11.9 µM). Moreover, in silico studies demonstrate maximum interactions of compounds in the enzyme’s active site. Furthermore, intermolecular interactions between compounds and enzyme atoms were examined using STD-NMR spectrophotometry. In parallel, molecular dynamics simulation was carried out to study compounds dynamic behavior within the urease binding region. Urease remained stable during most of the simulation time and ligands were bound in the protein active pocket as observed from the Root mean square deviation (RMSD) and ligand RMSD analyses. Furthermore, these compounds display interactions with the crucial residues, including His492 and Asp633, in 100 ns simulations. In the binding energy analysis, norepinephrine bitartrate exhibited the highest binding energy (-76.32 kcal/mol) followed by Ketoprofen (-65.56 kcal/mol) and terbutaline (-62.15 kcal/mol), as compared to acetohydroxamic acid (-52.86 kcal/mol). The current findings highlight the potential of drug repurposing as an effective approach for identifying novel anti-urease compounds.

Communicated by Ramaswamy H. Sarma

Keywords:

• Urease inhibition
• mechanistic studies
• molecular docking
• molecular dynamics
• urease isolation
• and STD-NMR

Acknowledgments

The authors would like to extend their gratitude to King Saud University (Riyadh, Saudi Arabia) for funding this research through Researchers supporting Project number (RSPD2023R693).

Availability of data and materials

All datasets on which the conclusions of the manuscript rely are presented in the paper.

Competing interests

The authors declare that they have no competing interests.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors would like to extend their gratitude to King Saud University (Riyadh, Saudi Arabia) for funding this research through Researchers supporting Project number (RSPD2023-R693).