title: Structural and docking studies of potent ethionamide boosters.
abstract: 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.
authors.affiliation: Department of Chemistry, Durham University, South Road, Durham DH1 3LE, England.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Tatum
authors.forename: Baptiste
authors.initials: B
authors.lastname: Villemagne
authors.forename: Nicolas
authors.initials: N
authors.lastname: Willand
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
authors.forename: John W
authors.initials: JW
authors.lastname: Liebeschuetz
authors.forename: Alain R
authors.initials: AR
authors.lastname: Baulard
authors.forename: Ehmke
authors.initials: E
authors.lastname: Pohl
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005000:Ethionamide / Q000737:chemistry* / Q000494:pharmacology*; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy*; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000187:drug effects*; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D011355:Prodrugs; D005000:Ethionamide
keywords: EthR; crystal structure; docking studies; structure-based drug design; tuberculosis