Insight into the mechanism of molecular interactions of the NDM metallo-beta-lactamase and cyclic boronate inhibition by molecular docking and molecular dynamics simulations

The spread and evolution of antimicrobial resistance (AMR) pose significant threats to public health, food safety, and sustainable development. Metallo-β-lactamases (MBLs), a class of carbapenemases that hydrolyze carbapenems—often considered last-resort antibiotics—are of particular concern and underscore the urgent need to develop effective inhibitors. Recent advancements in bicyclic boronate inhibitors represent significant progress toward this goal. Although the mechanistic basis of NDM-1 inhibition by bicyclic boronate inhibitors remains incompletely elucidated, this study systematically characterizes the binding profiles and intermolecular interaction landscapes between NDM-1 and four cyclic boronic acid-based inhibitors—vaborbactam (RPX7009), taniborbactam (VNRX 5133), xeruborbactam (QPX7728), and ledaborbactam (VNRX-5236). We established the NDM-1-mediated hydrolysis of two representative carbapenem antibiotics, meropenem and imipenem, as the reference system for comparative analysis. While conventional docking workflows often struggle to model metalloenzyme active sites accurately, the AMDock (Assisted Molecular Docking) platform, integrated with AutoDock’s optimized zinc force field, enables robust and reliable docking simulations for this enzyme family. Our AMDock-based molecular docking not only identified the critical NDM-1 binding-site residues governing hydrogen-bond networks with ligands, but also revealed that bicyclic boronate inhibitors show substantially greater binding stability than both carbapenems and their monocyclic boronate counterparts. A follow-up 100 ns all-atom molecular dynamics simulation in GROMACS provided atomistic-level evidence for this enhanced performance: RMSD, RMSF, radius of gyration, continuous hydrogen-bonding occupancy, and 2D free-energy landscape analyses all consistently supported the higher binding affinity of bicyclic boronates. Ultimately, this study characterizes two promising drug candidates, QPX7728 and VNRX-5133, as competitive inhibitors that can effectively rescue carbapenem activity against NDM-1 MBL-mediated antimicrobial resistance. This visualization elucidates interactions between NDM-1 and its two ligand classes—carbapenem antibiotics and cyclic boronate inhibitors. It reveals the stability and interaction strength underlying the distinct inhibition pattern of bicyclic boronate inhibitors in the enzyme’s active site, offering a promising strategy to combat antibiotic resistance.