𝐼𝑛 𝑆𝑖𝑙𝑖𝑐𝑜 Discovery of Natural Inhibitors against New Delhi Metallo-β-Lactamase-۱: A Step towards Combating Superbug Resistance

The emergence of New Delhi metallo-β-lactamase-۱ (NDM-۱) 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-۱-mediated resistance. In this study, a multi-tiered virtual screening approach was employed against a library of ۵۷,۴۲۳ 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, ZINC۹۵۹۰۹۶۹۶ demonstrated a more favorable binding affinity of -۱۰.۰۴۱ kcal/mol, outperforming the co-crystallized β-lactam antibiotic ampicillin (-۷.۰۸۷ kcal/mol). Binding interaction analysis reveals hydrogen bonding with Asn۲۲۰ and Lys۲۱۱, along with coordination with the catalytically essential Zn² ion (Zn۳۰۲), highlighting its potential as a non-β-lactam-based NDM-۱ inhibitor. A ۱۰۰ ns molecular dynamics simulation further confirmed the stability of the ZINC۹۵۹۰۹۶۹۶–NDM-۱ complex, as reflected by minimal fluctuations in RMSD and RMSF profiles. These results highlight ZINC۹۵۹۰۹۶۹۶ as a compelling lead candidate for developing non-β-lactam therapeutics targeting NDM-۱ β-lactamase.

کلیدواژه ها:

NDM-۱ ، Virtual screening ، natural inhibitors ، Docking ، MD simulation