Uncovering Novel VIM-2 Inhibitors from Fungal Sources Using Structure-Based Screening and Molecular Dynamics Approaches

Antibiotic resistance is a critical global health concern, with metallo-β-lactamases like Verona integron-encoded metallo-β-lactamase-2 (VIM-2) contributing to the breakdown of β-lactam antibiotics, including carbapenems. The increasing prevalence of VIM-2-mediated resistance highlights the urgent need for novel inhibitors. In this study, a structure-based virtual screening approach was employed to identify potential VIM-2 inhibitors from the Medicinal Fungal Secondary Metabolites and Therapeutics (MeFSAT) library. Molecular docking of 1,830 fungal-derived compounds, followed by molecular dynamics (MD) simulations, led to the identification of three promising candidates: MSID001033, MSID001081, and MSID001168. These compounds showed high docking scores and favorable interactions with the VIM-2 active site, forming stable complexes through π-π stacking, hydrogen bonding, and zinc coordination. MD simulations over 250 ns confirmed the structural stability of the complexes, supported by consistent RMSD, RMSF, and hydrogen bonding profiles. Further validation using MM-GBSA binding energy calculations, radial distribution function (RDF), salt bridge analysis, and anisotropic network model (ANM) cross-correlation reinforced their strong binding affinity. Overall, this study highlights fungal secondary metabolites as promising scaffolds for VIM-2 inhibition and demonstrates the effectiveness of integrated computational methods in accelerating early-stage antibiotic drug discovery.