TY - JOUR
T1 - Virtual Screening and Experimental Testing of B1 Metallo-β-lactamase Inhibitors
AU - Kang, Joon S.
AU - Zhang, Antonia L.
AU - Faheem, Mohammad
AU - Zhang, Charles J.
AU - Ai, Ni
AU - Buynak, John D.
AU - Welsh, William J.
AU - Oelschlaeger, Peter
N1 - Funding Information:
*E-mail: [email protected]. Phone: 909-469-8232. Fax: 909-469-5600. ORCID William J. Welsh: 0000-0002-5618-2072 Peter Oelschlaeger: 0000-0001-5949-9297 Author Contributions #These authors contributed equally to this study. Funding J.S.K., A.L.Z., M.F., C.J.Z., J.D.B., and P.O. received funding from the National Institutes of Health (R15 AI109624 to J.D.B.). N.A. and W.J.W. received funding from the National Institutes of Health (R21 GM081394 to W.J.W.). P.O. received intramural funding from the Western University of Health Sciences. Notes The authors declare no competing financial interest.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/9/24
Y1 - 2018/9/24
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jcim.8b00133
DO - 10.1021/acs.jcim.8b00133
M3 - Article
C2 - 30107123
AN - SCOPUS:85052388171
SN - 1549-9596
VL - 58
SP - 1902
EP - 1914
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 9
ER -