Structural and docking studies of potent ethionamide boosters

Tatum, Natalie; Villemagne, Baptiste; Willand, nicolas; Deprez, Benoit; Liebeschuetz, John; Baulard, Alain; Pohl, Ehmke

Document type :

Article dans une revue scientifique: Article original

DOI :

10.1107/S0108270113028126

Title :

Structural and docking studies of potent ethionamide boosters

Author(s) :

Tatum, Natalie [Auteur]
Villemagne, Baptiste [Auteur]

Biostructures et Decouverte de Medicament
Willand, nicolas [Auteur]

Biostructures et Decouverte de Medicament
Deprez, Benoit [Auteur]

Biostructures et Decouverte de Medicament
Liebeschuetz, John [Auteur]
Baulard, Alain [Auteur]

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

Journal title :

Acta Crystallographica Section C : Crystal Structure Communications [1968-2013]

Pages :

1243-1250

Publisher :

International Union of Crystallography

Publication date :

2013-10-24

ISSN :

0108-2701

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

Tuberculosis remains the second only to HIV as the leading cause of death by infectious disease worldwide, and was responsible for 1.4 million deaths globally in 2011. One of the essential drugs of the second-line ...
Show more >Tuberculosis remains the second only to HIV as the leading cause of death by infectious disease worldwide, and was responsible for 1.4 million deaths globally in 2011. One of the essential drugs of the second-line antitubercular regimen is the prodrug ethionamide, introduced in the 1960s. Ethionamide is primarily used in cases of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB due to severe adverse side effects. As a prodrug, ethionamide is bioactivated by EthA, a mono-oxygenase whose activity is repressed by EthR, a member of the TetR family of regulators. Previous studies have established that inhibition of EthR improves ethionamide potency. We report here the crystal structures of three EthR inhibitors at 0.8 Å resolution (3-oxo-3-{4-[3-(thiophen-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}propanenitrile (BDM31343), 4,4,4-trifluoro-1-{4-[3-(6-methoxy-1,3-benzothiazol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}butanone (BDM41325) and 5,5,5-trifluoro-1-{4-[3-(4-methanesulfonylphenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}pentanone (BDM41907)), and the docking studies undertaken to investigate possible binding modes. The results revealed two distinct orientations of the three compounds in the binding channel, a direct consequence of the promiscuous nature of the largely lipophilic binding site.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

Collections :

Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017

Source :

Harvested from HAL

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