In Silico Discovery of Natural Inhibitors against New Delhi Metallo Beta lactamase -1: A Step towards combating superbug Resistance

The emergence of New Delhi metallo-β-lactamase-1 (NDM-1) has become a major global health concern due to its ability to hydrolyze a wide spectrum of β-lactam antibiotics, including carbapenems, thereby limiting effective therapeutic options. Hence, the identification of potent non-β-lactam inhibitors is essential for overcoming NDM-1-mediated resistance. In the present study, a multi-tier virtual screening strategy was employed to identify potential inhibitors from 57,423 natural compounds obtained from the Traditional Chinese Medicine Database@Taiwan. Structure-based virtual screening was carried out using the Schrödinger suite through High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP) docking protocols. Drug-likeness and pharmacokinetic properties were evaluated based on Lipinski’s Rule of Five and Jorgensen’s Rule of Three.

Among the screened compounds, ten promising hits were identified, of which ZINC95909696 exhibited the highest binding affinity toward NDM-1 with a docking score of −10.041 kcal/mol, surpassing the co-crystallized ligand ampicillin (−7.087 kcal/mol). Molecular interaction studies revealed key hydrogen bonding interactions with Asn220 and Lys211, along with coordination with the catalytically important Zn²⁺ ion (Zn302), indicating its strong inhibitory potential against NDM-1. Furthermore, a 100 ns molecular dynamics simulation demonstrated the stability of the ZINC95909696–NDM-1 complex, supported by minimal deviations in RMSD and RMSF analyses. Overall, the findings suggest that ZINC95909696 may serve as a promising lead compound for the development of novel non-β-lactam therapeutics targeting NDM-1 β-lactamase.