Natalie J Tatum, Baptiste Villemagne, Nicolas Willand, Benoit Deprez, John W Liebeschuetz, Alain R Baulard, Ehmke Pohl
{"title":"强效乙硫酰胺助推器的结构与对接研究。","authors":"Natalie J Tatum, Baptiste Villemagne, Nicolas Willand, Benoit Deprez, John W Liebeschuetz, Alain R Baulard, Ehmke Pohl","doi":"10.1107/S0108270113028126","DOIUrl":null,"url":null,"abstract":"<p><p>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. </p>","PeriodicalId":7368,"journal":{"name":"Acta crystallographica. Section C, Crystal structure communications","volume":"69 Pt 11","pages":"1243-50"},"PeriodicalIF":0.8000,"publicationDate":"2013-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1107/S0108270113028126","citationCount":"11","resultStr":"{\"title\":\"Structural and docking studies of potent ethionamide boosters.\",\"authors\":\"Natalie J Tatum, Baptiste Villemagne, Nicolas Willand, Benoit Deprez, John W Liebeschuetz, Alain R Baulard, Ehmke Pohl\",\"doi\":\"10.1107/S0108270113028126\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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. </p>\",\"PeriodicalId\":7368,\"journal\":{\"name\":\"Acta crystallographica. Section C, Crystal structure communications\",\"volume\":\"69 Pt 11\",\"pages\":\"1243-50\"},\"PeriodicalIF\":0.8000,\"publicationDate\":\"2013-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1107/S0108270113028126\",\"citationCount\":\"11\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta crystallographica. Section C, Crystal structure communications\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1107/S0108270113028126\",\"RegionNum\":4,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2013/10/24 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta crystallographica. Section C, Crystal structure communications","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1107/S0108270113028126","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2013/10/24 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
Structural and docking studies of potent ethionamide boosters.
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.
期刊介绍:
Acta Crystallographica Section C: Structural Chemistry is continuing its transition to a journal that publishes exciting science with structural content, in particular, important results relating to the chemical sciences. Section C is the journal of choice for the rapid publication of articles that highlight interesting research facilitated by the determination, calculation or analysis of structures of any type, other than macromolecular structures. Articles that emphasize the science and the outcomes that were enabled by the study are particularly welcomed. Authors are encouraged to include mainstream science in their papers, thereby producing manuscripts that are substantial scientific well-rounded contributions that appeal to a broad community of readers and increase the profile of the authors.