A fragment merging approach towards the ...
Document type :
Article dans une revue scientifique: Article original
DOI :
PMID :
Title :
A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters
Author(s) :
Nikiforov, Petar [Auteur]
University of Cambridge [UK] [CAM]
Surade, Sachin [Auteur]
University of Cambridge [UK] [CAM]
Blaszczyk, Michal [Auteur]
University of Cambridge [UK] [CAM]
Delorme, Vincent [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Brodin, Priscille [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Baulard, Alain [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Blundell, Tom [Auteur]
University of Cambridge [UK] [CAM]
Abell, Chris [Auteur correspondant]
University of Cambridge [UK] [CAM]
University of Cambridge [UK] [CAM]
Surade, Sachin [Auteur]
University of Cambridge [UK] [CAM]
Blaszczyk, Michal [Auteur]
University of Cambridge [UK] [CAM]
Delorme, Vincent [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Brodin, Priscille [Auteur]

Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Baulard, Alain [Auteur]

Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Blundell, Tom [Auteur]
University of Cambridge [UK] [CAM]
Abell, Chris [Auteur correspondant]
University of Cambridge [UK] [CAM]
Journal title :
Organic & biomolecular chemistry
Pages :
2318-2326
Publisher :
Royal Society of Chemistry
Publication date :
2016
ISSN :
1477-0520
English keyword(s) :
Crystallography
Structure-Activity Relationship
X-Ray
Ethionamide
chemistry
pharmacology
Hydrophobic and Hydrophilic Interactions
Structure-Activity Relationship
X-Ray
Ethionamide
chemistry
pharmacology
Hydrophobic and Hydrophilic Interactions
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide ...
Show more >With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial transcriptional repressor protein EthR is an attractive therapeutic strategy. Herein we report the use of a fragment based drug discovery approach for the structure-guided systematic merging of two fragment molecules, each binding twice to the hydrophobic cavity of EthR from M. tuberculosis. These together fill the entire binding pocket of EthR. We elaborated these fragment hits and developed small molecule inhibitors which have a 100-fold improvement of potency in vitro over the initial fragments.Show less >
Show more >With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial transcriptional repressor protein EthR is an attractive therapeutic strategy. Herein we report the use of a fragment based drug discovery approach for the structure-guided systematic merging of two fragment molecules, each binding twice to the hydrophobic cavity of EthR from M. tuberculosis. These together fill the entire binding pocket of EthR. We elaborated these fragment hits and developed small molecule inhibitors which have a 100-fold improvement of potency in vitro over the initial fragments.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
Source :
Files
- c5ob02630j
- Open access
- Access the document
- document
- Open access
- Access the document
- c5ob02630j.pdf%3B
- Open access
- Access the document
- document
- Open access
- Access the document
- c5ob02630j.pdf%3B
- Open access
- Access the document