Ligand efficiency driven design of new ...
Document type :
Article dans une revue scientifique
DOI :
PMID :
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Title :
Ligand efficiency driven design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging, and linking approaches
Author(s) :
Villemagne, Baptiste [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Flipo, Marion [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Blondiaux, Nicolas [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Institut Pasteur de Lille
Crauste, Céline [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Malaquin, Sandra [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Leroux, Florence [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Piveteau, Catherine [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Villeret, Vincent [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Brodin, Priscille [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Villoutreix, Bruno O. [Auteur]
Molécules Thérapeutiques in silico [MTI]
Sperandio, Olivier [Auteur]
Molécules Thérapeutiques in silico [MTI]
Soror, Sameh H. [Auteur]
VIB-VUB Center for Structural Biology [Bruxelles]
Wohlkönig, Alexandre [Auteur]
VIB-VUB Center for Structural Biology [Bruxelles]
Wintjens, René [Auteur]
Faculté de Pharmacie [Bruxelles] [ULB]
Deprez, Benoit [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Baulard, Alain [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
willand, nicolas [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Flipo, Marion [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Blondiaux, Nicolas [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Institut Pasteur de Lille
Crauste, Céline [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Malaquin, Sandra [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Leroux, Florence [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Piveteau, Catherine [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Villeret, Vincent [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Brodin, Priscille [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Villoutreix, Bruno O. [Auteur]
Molécules Thérapeutiques in silico [MTI]
Sperandio, Olivier [Auteur]
Molécules Thérapeutiques in silico [MTI]
Soror, Sameh H. [Auteur]
VIB-VUB Center for Structural Biology [Bruxelles]
Wohlkönig, Alexandre [Auteur]
VIB-VUB Center for Structural Biology [Bruxelles]
Wintjens, René [Auteur]
Faculté de Pharmacie [Bruxelles] [ULB]
Deprez, Benoit [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Baulard, Alain [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
willand, nicolas [Auteur]
Biostructures et Decouverte de Medicament
Institut Pasteur de Lille
Journal title :
Journal of medicinal chemistry
Abbreviated title :
J. Med. Chem.
Volume number :
57
Pages :
4876-4888
Publication date :
2014-06-12
ISSN :
1520-4804
English keyword(s) :
Surface Plasmon Resonance
Cell Line
X-ray Crystallography
Repressor Proteins
Structure-Activity Relationship
Bacterial Proteins
Animals
Antitubercular Agents
Mycobacterium tuberculosis
Thiazoles
Protein Binding
Mice
Molecular Docking Simulation
Benzamides
Cell Line
X-ray Crystallography
Repressor Proteins
Structure-Activity Relationship
Bacterial Proteins
Animals
Antitubercular Agents
Mycobacterium tuberculosis
Thiazoles
Protein Binding
Mice
Molecular Docking Simulation
Benzamides
HAL domain(s) :
Chimie/Chimie théorique et/ou physique
English abstract : [en]
Tuberculosis remains a major cause of mortality and morbidity, killing each year more than one million people. Although the combined use of first line antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol) is ...
Show more >Tuberculosis remains a major cause of mortality and morbidity, killing each year more than one million people. Although the combined use of first line antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol) is efficient to treat most patients, the rapid emergence of multidrug resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. Mycobacterial transcriptional repressor EthR is a key player in the control of second-line drugs bioactivation such as ethionamide and has been shown to impair the sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. As a way to identify new potent ligands of this protein, we have developed fragment-based approaches. In the current study, we combined surface plasmon resonance assay, X-ray crystallography, and ligand efficiency driven design for the rapid discovery and optimization of new chemotypes of EthR ligands starting from a fragment. The design, synthesis, and in vitro and ex vivo activities of these compounds will be discussed.Show less >
Show more >Tuberculosis remains a major cause of mortality and morbidity, killing each year more than one million people. Although the combined use of first line antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol) is efficient to treat most patients, the rapid emergence of multidrug resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. Mycobacterial transcriptional repressor EthR is a key player in the control of second-line drugs bioactivation such as ethionamide and has been shown to impair the sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. As a way to identify new potent ligands of this protein, we have developed fragment-based approaches. In the current study, we combined surface plasmon resonance assay, X-ray crystallography, and ligand efficiency driven design for the rapid discovery and optimization of new chemotypes of EthR ligands starting from a fragment. The design, synthesis, and in vitro and ex vivo activities of these compounds will be discussed.Show less >
Language :
Anglais
Audience :
Non spécifiée
Administrative institution(s) :
CHU Lille
CNRS
Inserm
Université de Lille
Institut Pasteur de Lille
CNRS
Inserm
Université de Lille
Institut Pasteur de Lille
Collections :
Research team(s) :
Biologie structurale et intégrative
Submission date :
2020-02-12T15:11:28Z
2021-03-11T13:52:08Z
2021-03-11T13:52:08Z