In Silico Discovery of Natural Inhibitors against New Delhi Metallo-Beta-Lactamase-l: A Step towards Combating Superbug Resistance

The emergence of New Delhi metallo-/Mactamase-l (NDM-1) leads to a significant global health threat due to its abilityto hydrolyze a broad range of lactam antibiotics, including carbapenems, leaving few alternatives for therapy.
Therefore, identifying non-/beta-lactam inhibitors is crucial for combating NDM-1-mediated resistance. In this study, a multi-tiered virtual screeningapproachwas 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 Schrodinger 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.
Amongthem, ZINC95909696 demonstrated a morefavorable bindingaffinity of -10.041 kcal/mol,outperformingthe co-crystallized/beta-lactam antibioticampicillin (-7.087 kcal/mol). Binding interaction analysis reveals hydrogen bonding with Asn220 and Lys211, along with coordinationwiththe catalytically essential Zn2 ion (Zn302), highlighting its potential as a non-/?-lactam-basedNDM-1 inhibitor. A 100 ns molecular dynamics simulation further confirmed the stability of the Z1NC95909696-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-/beta-lactam therapeutics targeting NDM-1 p-lactamase.