A common binding mode that may facilitate the design of novel broad-spectrum inhibitors against metallo-β-lactamases

Abstract

Multidrug resistance caused by metallo-β-lactamases (MBLs) remains a therapeutic challenge owing to their broad hydrolytic spectrum on β-lactams, and current β-lactamase inhibitors are ineffective against MBL-carrying superbugs. In this study, we discovered a series of potential inhibitors against various MBLs through a hybrid in silico protocol that combines support vector machine, protein–ligand interaction fingerprint (PLIF) analysis, and molecular docking. These compounds were shown to have a common binding mode. PLIF analysis and molecular docking demonstrated that the sulfonyl oxygens and the amide oxygen coordinated to zinc ions in a similar fashion, indicating the importance of such structural characteristics in the design of broad-spectrum inhibitors against MBLs. In addition, the carbon atom connecting the sulfonyl amide and the nitrogen heterocycle played an important role in ligand flexibility, allowing the rotation of the aromatic ring to accommodate the hydrophobic pockets in the binding site of different subclasses of MBLs. These findings may pave the way to the design of novel broad-spectrum inhibitors against MBLs.