Virtual Screening and Experimental Testing of B1 Metallo-β-lactamase Inhibitors.

The global rise of metallo-beta-lactamases (MBLs) is problematic due to their ability to inactivate most beta-lactam antibiotics. MBL inhibitors that could be coadministered with and restore the efficacy of beta-lactams are highly sought after. In this study, we employ virtual screening of candidate MBL inhibitors without thiols or carboxylates to avoid off-target effects using the Avalanche software package, followed by experimental validation of the selected compounds. As target enzymes, we chose the clinically relevant B1 MBLs NDM-1, IMP-1, and VIM-2. Among 32 compounds selected from an approximately 1.5 million compound library, 6 exhibited IC50 values less than 40 mu M against NDM-1 and/or IMP-1. The most potent inhibitors of NDM-1, IMP-1, and VIM-2 had IC50 values of 19 +/- 2, 14 +/- 1, and 50 +/- 20 mu M, respectively. While chemically diverse, the most potent inhibitors all contain combinations of hydroxyl, ketone, ester, amide, or sulfonyl groups. Docking studies suggest that these electron-dense moieties are involved in Zn(II) coordination and interaction with protein residues. These novel scaffolds could serve as the basis for further development of MBL inhibitors. A procedure for renaming NDM-1 residues to conform to the class B beta-lactamase (BBL) numbering scheme is also included.