Computational Analysis of Novel NDM-1 Inhibitors: Absorption, Distribution, Metabolism, Excretion, and Toxicity Evaluation, Molecular Docking, and Molecular Dynamics of Cyclic Borate Derivatives and Chromones

The increasing resistance to antibiotics poses an urgent challenge in public health, particularly due to the action of metallo-β-lactamase NDM-1, which is capable of hydrolyzing the β-lactam ring present in most conventional antibiotics, including carbapenems. Since these compounds have traditionally been the primary line of defense against resistant bacterial infections, it is crucial to explore new chemical structures that can circumvent this inactivation mechanism and act as effective inhibitors of NDM-1. In this study, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of 20 potential inhibitors were evaluated, identifying 15 molecules with favorable oral bioavailability profiles and low toxicity. Among them, chromone derivatives and cyclic borates stood out for their therapeutic potential. The estimation of the binding energy between NDM-1 and these compounds, using the AutoDock4Zn force field, yielded values of −12.16, −11.81, and −11.46 kcal/mol for compounds M10, M9, and M7, respectively. To further analyze the conformational stability and flexibility of the complexes, molecular dynamics simulations were performed using GROMACS for 250 ns. The results revealed that the new inhibitors establish stable interactions with NDM-1, as evidenced by key parameters such as root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and hydrogen bond formation throughout the simulation time. When comparing these findings with the reference NDM-1-Meropenem system, it was observed that the proposed compounds could offer a promising alternative to antibiotic resistance. These results suggest that M10, M9, and M7 are potential candidates for synthesis and validation study in vivo assays to assess their efficacy as NDM-1 inhibitors.