title: Probing metallo-β-lactamases with molecular fragments identified by consensus docking.
abstract: Bacterial resistance mediated by metallo-β-lactamases (MBLs) is a major problem for the treatment of infections. An MBL inhibitor could restore the potency of β-lactam antibiotics. Fragment-based design might deliver valuable starting points for the discovery of novel MBL inhibitors. In this study, we chose an in silico approach to search for fragments able to bind and inhibit NDM-1, VIM-1, and IMP-7. We used consensus docking to identify low molecular weight compounds from a commercially available library. Most promising compounds were evaluated in a sensitive fluorescence-based activity assay and by the orthogonal biophysical technique saturation transfer difference (STD)-NMR. (1)H-(15)N chemical shift perturbation NMR was used to confirm the reversible binding and measure the dissociation constant of the most promising compound qualifying it as a high-quality starting point for further optimization.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany.
authors.forename: Franca-Maria
authors.initials: FM
authors.lastname: Klingler
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Moser
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Büttner
authors.affiliation: Institute of Medical Microbiology and Infection Control, Goethe University, Paul-Ehrlich-Straße 40, 60596 Frankfurt, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wichelhaus
authors.affiliation: Institute of Biophysical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Löhr
authors.affiliation: Institute of Biophysical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Dötsch
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany. Electronic address: proschak@pharmchem.uni-frankfurt.de.
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
mesh_terms: D001578:Benzopyrans / Q000737:chemistry; D003198:Computer Simulation; D005453:Fluorescence; D062105:Molecular Docking Simulation; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors / Q000737:chemistry*; D001618:beta-Lactamases / Q000737:chemistry*
chemical_list: D001578:Benzopyrans; D065093:beta-Lactamase Inhibitors; C417264:VIM-1 metallo-beta-lactamase; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1
keywords: Antibiotic resistance; Consensus docking; Fragment-based; Metallo-β-lactamase (MBL); NMR