Deciphering the interaction landscape of NDM-1 with a novel β-lactam-based inhibitor: implications for rational drug design.

The rise of antibiotic resistance mediated by New Delhi metallo-β-lactamase-1 (NDM-1) poses a major challenge to antimicrobial therapy. In this study, structure-based virtual screening, molecular docking, post-docking MM-GBSA rescoring, and 1 μs molecular dynamics (MD) simulations were used to prioritize β-lactam-derived inhibitors of NDM-1. Three compounds were advanced for energetic and dynamic evaluation. Among them, 5YLP_14953 showed the most favorable single-structure Prime MM-GBSA score (- 73.38 kcal/mol). These calculated values are used for relative ranking and should not be interpreted as experimentally measured absolute binding free energies. Interaction and trajectory analyses indicated persistent contacts with the dinuclear Zn2+ center and catalytic-site residues, including His122, Asp124, Cys208, and His250. The ligand-bound systems retained stable global folds, while local fluctuations were concentrated mainly in terminal and loop regions. The results support 5YLP_14953, 5YLP_10079, and 5YLP_27558 as computationally prioritized leads for experimental testing. Because the study used one trajectory per complex and did not include apo-NDM-1 or a known-inhibitor control, the conclusions are limited to pose stability and comparative computational prioritization.