Structural and docking studies of potent ethionamide boosters

• Published in: Acta crystallographica. Section C, Crystal structure communications Vol. 69; no. 11; pp. 1243 - 1250
• Main Authors: Tatum, Natalie J., Villemagne, Baptiste, Willand, Nicolas, Deprez, Benoit, Liebeschuetz, John W., Baulard, Alain R., Pohl, Ehmke
• Format: Journal Article
• Language: English
• Published: 5 Abbey Square, Chester, Cheshire CH1 2HU, England International Union of Crystallography 01.11.2013; Wiley Subscription Services, Inc
• Subjects: Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Binding; Binding Sites; Channels; Chemical compounds; Crystal structure; Crystallography, X-Ray; Death; Docking; docking studies; Drugs; Ethionamide - chemistry; Ethionamide - pharmacology; EthR; Extensively Drug-Resistant Tuberculosis - drug therapy; Infectious diseases; Inhibitors; Life Sciences; Models, Molecular; Mycobacterium tuberculosis - chemistry; Mycobacterium tuberculosis - drug effects; Prodrugs - chemistry; Prodrugs - pharmacology; structure-based drug design; Tuberculosis; EthR; crystal structure; structure-based drug design; docking studies; tuberculosis
• ISSN: 0108-2701; 1600-5759
• DOI: 10.1107/S0108270113028126

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.