Tatum Natalie J, Villemagne Baptiste, Willand Nicolas, Deprez Benoit, Liebeschuetz John W, Baulard Alain R, Pohl Ehmke
Department of Chemistry, Durham University, South Road, Durham DH1 3LE, England.
Acta Crystallogr C. 2013 Nov;69(Pt 11):1243-50. doi: 10.1107/S0108270113028126. Epub 2013 Oct 24.
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.
结核病仍然是全球仅次于艾滋病的第二大传染病致死病因，2011年全球有140万人死于该病。二线抗结核治疗方案的基本药物之一是20世纪60年代引入的前体药物乙硫异烟胺。由于严重的不良副作用，乙硫异烟胺主要用于耐多药（MDR）和广泛耐药（XDR）结核病病例。作为一种前体药物，乙硫异烟胺被EthA生物激活，EthA是一种单加氧酶，其活性受到TetR家族调节因子成员EthR的抑制。先前的研究已证实抑制EthR可提高乙硫异烟胺的效力。我们在此报告了三种EthR抑制剂在0.8 Å分辨率下的晶体结构（3-氧代-3-{4-[3-(噻吩-2-基)-1,2,4-恶二唑-5-基]哌啶-1-基}丙腈（BDM31343）、4,4,4-三氟-1-{4-[3-(6-甲氧基-1,3-苯并噻唑-2-基)-1,2,4-恶二唑-5-基]哌啶-1-基}丁酮（BDM41325）和5,5,5-三氟-1-{4-[3-(4-甲磺酰基苯基)-1,2,4-恶二唑-5-基]哌啶-1-基}戊酮（BDM41907）），以及为研究可能的结合模式而进行的对接研究。结果揭示了这三种化合物在结合通道中的两种不同取向，这是主要为亲脂性的结合位点的混杂性质的直接结果。
