Introduction: Antibiotic resistance driven by β-lactamases, particularly AmpC β-lactamase in Escherichia coli, poses a significant threat to global health.
Aims: This study investigates the inhibitory potential of phytochemicals from Acacia, Moringa oleifera, and Curcuma longa against AmpC β-lactamase using computational methods.
Materials and Methods: The 3D structure of E. coli AmpC β-lactamase was prepared by removing heteroatoms, while antibacterial phytochemicals from PubChem were energy-minimized and converted to PDBQT format. Molecular docking utilized a grid-box-focused active site to predict ligand-receptor binding affinities and conformations. Interactions were visualized, and drug-likeness and ADMET profiles (ADMETLab3.0) were computationally assessed.
Results: β-amyrin exhibited the strongest binding affinity (-9.9 kcal/mol), surpassing the control compound ceftazidime (-8.5 kcal/mol), with critical interactions involving Tyr221 and Lys315. Sitosterol also showed promising binding energies (-9.1 kcal/mol), forming hydrogen bonds and π-π interactions with key residues. Drug-likeness screening via DruLiTo confirmed compliance with Lipinski’s Rule of Five for all compounds, except minor violations in molecular weight (curcumin) and hydrogen bond donors (β-amyrin). ADMET profiling using ADMETLab 3.0 revealed favourable pharmacokinetic properties, including high gastrointestinal absorption for β-amyrin and sitosterol. However, toxicity risks such as hepatotoxicity (β-amyrin, betulin) and genotoxicity (AMES test positivity) were noted. Molecular interaction analysis highlighted targeting of critical active-site residues (Tyr150, Tyr221, and Ser64), suggesting disruption of catalytic activity
Conclusion: These findings position β-amyrin as a lead compound for further development, despite requiring structural optimization to mitigate toxicity. The study underscores the potential of plant-derived compounds to combat AmpC-mediated resistance, offering a promising avenue for novel inhibitor design