In Silico Discovery of Natural Inhibitors against New Delhi Metallo-β-Lactamase-1: A Step towards Combating Superbug Resistance
نویسندگان
1 Department of Pharmaceutical Chemistry & Analysis, School of Pharmaceutical Sciences, Vels Institute of Science, Technology & Advanced Studies, Pallavaram, Chennai - 600 117, Tamil Nadu, India
2 Department of Pharmaceutical Chemistry, KMCH College of Pharmacy, Kalapatti road, Coimbatore -641048, Tamil Nadu, India
3 Research Scholar, Department of Pharmaceutical Chemistry & Analysis, School of Pharmaceutical Sciences, Vels Institute of Science, Technology & Advanced Studies, Pallavaram, Chennai - 600 117, Tamil Nadu, India
4 Department of Pharmacy Practice, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, Pallavaram, Chennai - 600 117, India
5 Department of Pharmacology, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, Pallavaram, Chennai - 600 117, India
6 Department of Department of Radiology, Vels Medical College and Hospital, Manjankaranai, Thiruvallur - 601 102, India
7 Department of Pharmacognosy, School of Pharmaceutical Sciences, Vels Institute of Science Technology and Advanced Studies, Old Pallavaram, Chennai 117, India
8 Department of Pharmaceutical Chemistry & Analysis, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, Pallavaram, Chennai - 600 117, India
doi
10.48309/chemm.2025.526024.1966چکیده
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.
