Molecular Docking and Molecular Dynamics Simulations to Introduce New Inhibitors for Ambler Class C of β-lactamase Enzymes

Abstract

β-lactam antibiotics account for nearly 60% of global antibiotic use and are vital in treating bacterial infections by inhibiting bacterial  cell wall synthesis. However, bacterial resistance has significantly increased due to the production of β-lactamase enzymes, which  hydrolyze the β-lactam ring and deactivate the drug. To counter this resistance, β-lactam antibiotics are often administered with β-lactamase inhibitors. In this study, molecular docking and molecular dynamics simulations were used to identify new inhibitors of class C β-lactamase enzymes. A total of 1177 compounds were initially selected based on structural similarity to known drugs, followed by ADMET filtering, which reduced the number to 433 candidates. These compounds were docked with five target β-lactamase proteins. Five compounds—ZINC29247885 and ZINC22925503 (from EDTA derivatives), ZINC207616107 and ZINC220912466 (from Nacubactam analogs), and ZINC199517773 (from Vaborbactam subgroup)—showed the highest docking scores. Their performance was compared with that of β-lactam antibiotics to evaluate their potential in combination therapies. Molecular dynamics simulations for 100 ns were conducted to assess the stability of the ligand-receptor complexes. The results suggest that these compounds are promising β-lactamase inhibitors and could enhance the efficacy of β-lactam antibiotics in clinical applications by overcoming bacterial resistance.