Virtual Screening and Experimental Testing of B1 Metallo-ß-lactamase Inhibitors.
J Chem Inf Model
; 58(9): 1902-1914, 2018 09 24.
Article
em En
| MEDLINE
| ID: mdl-30107123
ABSTRACT
The global rise of metallo-ß-lactamases (MBLs) is problematic due to their ability to inactivate most ß-lactam antibiotics. MBL inhibitors that could be coadministered with and restore the efficacy of ß-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 ß-lactamase (BBL) numbering scheme is also included.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Beta-Lactamases
/
Avaliação Pré-Clínica de Medicamentos
/
Inibidores de beta-Lactamases
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Revista:
J Chem Inf Model
Assunto da revista:
INFORMATICA MEDICA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos