Exploring the in vitro urease inhibitory potential, molecular docking and dynamics simulations investigation of
Obaid Ullah1, Aftab Alam2, Muhammad Ayaz1
1Department of Chemistry, University of Malakand, Khyber Pakhtunkhwa, Pakistan.
Aims:
To biologically evaluate a series of hydrazide derivatives of mefenamic acid as anti-urease agents, elucidating their mechanism of action through integrated computational and experimental approaches.
Method:
The inhibitory mechanism was interpreted through comprehensive computational studies: molecular docking to identify binding modes within the catalytic site of H. pylori urease (PDB: 4UBP), Density Functional Theory (DFT) calculations to evaluate global chemical reactivity and frontier molecular orbitals (FMOs), and Molecular Dynamics (MD) simulations to confirm complex stability. Preliminary pharmacokinetic and toxicity profiles were predicted in silico.
Results:
Compound 2a, featuring a para-nitro substituent, emerged as the most potent inhibitor (IC50 = 21.33 ± 0.01 µM), outperforming the standard thiourea (IC50 = 22.36 ± 0.30 µM).
Discussion:
DFT analysis revealed 2a possessed the lowest energy gap (Δε = 2.417 eV) and highest electrophilicity index (ω = 8.658 eV), correlating with superior reactivity and charge-transfer capacity. Molecular docking confirmed competitive inhibition with 2a forming key hydrogen bonds with Arg339 and His323.
Conclusion:
This work identifies 2a as a potent, and competitive urease inhibitor. The integrated experimental, ADMET and computational strategy provides a robust molecular blueprint for its activity, positioning it as a promising lead candidate for developing new therapeutic agents against urease-related pathologies.
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