Virtual screening and molecular dynamics simulations reveal insights into drug repurposing strategies against New Delhi metallo-β-lactamase
Sandip Dolui, Animesh Mondal, Kaushik Biswas, Kamalika Mazumder · Letters in Drug Design & Discovery · 2025
Antibiotic resistance continues to pose a serious threat to public health globally, drawing attention from health agencies and governments worldwide. Among the various resistance mechanisms, the emergence of New Delhi Metallo-β-lactamase-1 (NDM-1) and its variants is particularly concerning, as these enzymes deactivate a broad spectrum of β-lactam antibiotics, including carbapenems, which are often used as last-line treatments. Addressing this challenge requires the identification of compounds capable of restoring the activity of existing antibiotics. This study aimed to identify potential NDM-1 inhibitors from FDA-approved drugs using pharmaco-informatics approaches, with the goal of repurposing existing compounds to combat resistance to β-lactam antibiotics. We used pharmaco-informatics tools to identify potential NDM-1 inhibitors from a curated set of FDA-approved drugs. Using a combination of molecular docking and molecular dynamics (MD) simulations, we screened 192 approved compounds along with standard antibiotics and known inhibitors. Docking analysis identified meropenem and four repurposed drugs zavegepant, ubrogepant, atogepant, and tucatinib as the top candidates with favourable binding affinities for NDM-1. To gain a deeper discernment of these drug-protein complexes, we conducted MD simulations. Trajectory analyses, including root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and hydrogen bond monitoring, confirmed the structural stability of these interactions over time. The findings suggest that zavegepant, tucatinib, atogepant, and ubrogepant are promising candidates for repurposing as NDM-1 inhibitors. These results not only highlight their potential to combat resistance to β-lactam antibiotics but also showcase an initial point for future therapeutic development against multidrug-resistant bacterial infections.