Comprehensive Computational Exploration of Copper (II)–Benzimidazole Complexes as DNA Gyrase B Inhibitors: Integrated Molecular Modeling and Molecular Dynamics Approaches

The increasing prevalence of antimicrobial resistance, particularly among Gram-negative bacteria, emphasizes the critical need for new therapeutic approaches. This study investigated the inhibitory potential of four copper (II)-benzimidazole complexes against Escherichia coli DNA gyrase B, a key enzyme involved in bacterial DNA topology, which is a well-known target for antibacterial drug discovery. The stability and interaction behavior of the complexes were evaluated using a comprehensive computational pipeline that included molecular docking, MM/GBSA binding energy estimation, and 200 ns molecular dynamics simulations. Docking revealed that all the candidates fit comfortably within the ATP-binding site, with notable interactions involving residues such as Arg136, His55, Glu50, and Asp49. Dynamic analyses, such as RMSD, RMSF, radius of gyration, PCA, and free energy landscape mapping, revealed the conformational responses of the enzyme-ligand complexes. Cu(C14H12BrN3O2)2 (compound 4) consistently outperformed other compounds in terms of structural stability, conformational sampling restrictions, and thermodynamic favorability. This was further supported by MM/GBSA calculations, which revealed that compound 4 had a significantly lower binding free energy than those of the other complexes. Overall, this study identified compound 4 as a promising scaffold for further development as a DNA gyrase B inhibitor. These results highlight the importance of copper (II)-benzimidazole systems in antimicrobial drug design and provide a molecular foundation for future experimental and structural refinement efforts.