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

Joon S. Kang, Antonia L. Zhang, Mohammad Faheem, Charles J. Zhang, Ni Ai, John D. Buynak, William J. Welsh, Peter Oelschlaeger

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

The global rise of metallo-β-lactamases (MBLs) is problematic due to their ability to inactivate most β-lactam antibiotics. MBL inhibitors that could be coadministered with and restore the efficacy of β-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 μM 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 μM, 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 β-lactamase (BBL) numbering scheme is also included.

Original languageEnglish (US)
Pages (from-to)1902-1914
Number of pages13
JournalJournal of Chemical Information and Modeling
Volume58
Issue number9
DOIs
StatePublished - Sep 24 2018

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Chemical Engineering
  • Computer Science Applications
  • Library and Information Sciences

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