Abyssomicin W and Neoabyssomicin B are Potential Inhibitors of New Delhi Metallo‑β‑Lactamase‑1 (NDM ‑1): A Computational Approach

Background: Antibiotic resistance in bacteria mediated by New Delhi Metallo‑β‑lactamase (NDM) is a global threat to human health with an enormous economic burden. NDM can hydrolyze all the β‑lactam core‑containing antibiotics including carbapenems, which are regarded as last resort antibiotics. Materials and Methods: A library of Abyssomicins was virtually screened to identify novel non‑β‑lactam ring‑containing inhibitors of NDM‑1. Different computational approaches such as molecular modeling, virtual screening, molecular docking, molecular dynamics simulation, ADMET profiling, and free energy calculations were utilized for this purpose. Results: Virtual screening and ADMET profiling shortlisted Abyssomicin W and Neoabyssomicin B as the most promising candidate molecules. An in‑depth analysis of protein‑ligand interactions by molecular docking revealed that both ligands bind the active site of NDM‑1. The identified inhibitors interacted with key catalytic residues as well as other residues around the active site of NDM‑1. Hydrogen bonding and hydrophobic interactions played a significant role in stabilizing the protein‑inhibitor complexes. The docking energy of NDM‑1‑Abyssomicin W, and NDM‑1‑Neoabyssomicin B complexes were − 9.6 kcal/mol and − 9.5 kcal/mol, respectively, which were higher than NDM‑1‑Methicillin (control) complex (−7.3 kcal/mol). Molecular dynamics simulation and free energy calculations by MM‑PBSA also confirmed the stability of NDM‑1‑Abyssomicin W, and NDM‑1‑Neoabyssomicin B complexes. Conclusion: The findings of this study suggest that Abyssomicins serve as potential inhibitors of NDM‑1. However, these results need to be validated in vitro and in vivo. This study may serve as a basis for further developing Abyssomicins as novel inhibitors of β‑lactamases.