Fragment-based drug discovery; High throughput virtual screening; Metallo-β-lactamase; NDM-1; STD NMR screening; Anti-Bacterial Agents; beta-Lactamase Inhibitors; beta-Lactams; beta-Lactamases; beta-lactamase NDM-1; Anti-Bacterial Agents/chemistry; Anti-Bacterial Agents/pharmacology; Drug Discovery; beta-Lactamase Inhibitors/chemistry; beta-Lactamase Inhibitors/pharmacology; beta-Lactamases/chemistry; Pharmacology; Organic Chemistry; General Medicine
Abstract :
[en] Hydrolysis of β-lactam drugs, a major class of antibiotics, by serine or metallo-β-lactamases (SBL or MBL) is one of the main mechanisms for antibiotic resistance. New Delhi Metallo-β-lactamase-1 (NDM-1), an acquired metallo-carbapenemase first reported in 2009, is currently considered one of the most clinically relevant targets for the development of β-lactam-β-lactamase inhibitor combinations active on NDM-producing clinical isolates. Identification of scaffolds that could be further rationally pharmacomodulated to design new and efficient NDM-1 inhibitors is thus urgently needed. Fragment-based drug discovery (FBDD) has become of great interest for the development of new drugs for the past few years and combination of several FBDD strategies, such as virtual and NMR screening, can reduce the drawbacks of each of them independently. Our methodology starting from a high throughput virtual screening on NDM-1 of a large library (more than 700,000 compounds) allowed, after slicing the hit molecules into fragments, to build a targeted library. These hit fragments were included in an in-house untargeted library fragments that was screened by Saturation Transfer Difference (STD) Nuclear Magnetic Resonance (NMR). 37 fragments were finally identified and used to establish a pharmacophore. 10 molecules based on these hit fragments were synthesized to validate our strategy. Indenone 89 that combined two identified fragments shows an inhibitory activity on NDM-1 with a Ki value of 4 μM.
Disciplines :
Microbiology Biochemistry, biophysics & molecular biology Life sciences: Multidisciplinary, general & others
Author, co-author :
Caburet, Jérémy; Univ. Grenoble Alpes, CNRS, DPM, 38000, Grenoble, France, Univ. Grenoble Alpes, CNRS, CEA, LCBM, 38000, Grenoble, France
Boucherle, Benjamin; Univ. Grenoble Alpes, CNRS, DPM, 38000, Grenoble, France
Bourdillon, Sofiane; Univ. Grenoble Alpes, CNRS, DPM, 38000, Grenoble, France
Simoncelli, Giorgia; Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena, 53100, Siena, Italy
Verdirosa, Federica; Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena, 53100, Siena, Italy
Krimm, Isabelle; Small Molecules for Biological Targets Team, Centre de recherche en cancérologie de Lyon, Centre Léon Bérard, CNRS 5286, INSERM 1052, Université Claude Bernard Lyon 1, Univ Lyon, Lyon, 69373, France
This work has been partially supported by Labex Arcane and CBH-EUR-GS (ANR-17-EURE-0003). The authors wish to acknowledge the ICMG Nanobio Platform (FR 2607), on which the NMR and MS experiment were performed.
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