in silico discovery of natural inhibitors against new delhi metallo-β-lactamase-1: a step towards combating superbug resistance

The emergence of new delhi metallo-β-lactamase-1 (ndm-1) leads to a significant global health threat due to its ability to hydrolyze a broad range of β-lactam antibiotics, including carbapenems, leaving few alternatives for therapy. therefore, identifying non-β-lactam inhibitors is crucial for combating ndm-1-mediated resistance. in this study, a multi-tiered virtual screening approach was employed against a library of 57,423 natural compounds from the traditional chinese medicine database@taiwan. structure-based virtual screening, including high throughput virtual screening (htvs), standard precision (sp), and extra-precision (xp) docking protocols, was performed using the schrödinger suite. drug-likeness was evaluated using lipinski’s rule of five and jorgensen’s rule of three, leading to the identification of ten promising hits. among them, zinc95909696 demonstrated a more favorable binding affinity of -10.041 kcal/mol, outperforming the co-crystallized β-lactam antibiotic ampicillin (-7.087 kcal/mol). binding interaction analysis reveals hydrogen bonding with asn220 and lys211, along with coordination with the catalytically essential zn² ion (zn302), highlighting its potential as a non-β-lactam-based ndm-1 inhibitor. a 100 ns molecular dynamics simulation further confirmed the stability of the zinc95909696–ndm-1 complex, as reflected by minimal fluctuations in rmsd and rmsf profiles. these results highlight zinc95909696 as a compelling lead candidate for developing non-β-lactam therapeutics targeting ndm-1 β-lactamase.