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Inhibition of Mycobacterium tuberculosis Dethiobiotin Synthase (MtDTBS): Toward Next-Generation Antituberculosis Agents
ACS Chemical Biology ( IF 4 ) Pub Date : 2021-09-17 , DOI: 10.1021/acschembio.1c00491
Nicholas C Schumann 1, 2, 3 , Kwang Jun Lee 1, 2, 3 , Andrew P Thompson 4 , Wanisa Salaemae 5 , Jordan L Pederick 6 , Thomas Avery 1, 2, 3 , Birgit I Gaiser 2 , James Hodgkinson-Bean 6 , Grant W Booker 6 , Steven W Polyak 6 , John B Bruning 6 , Kate L Wegener 6 , Andrew D Abell 1, 2, 3
Affiliation  

Mycobacterium tuberculosis dethiobiotin synthase (MtDTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, M. tuberculosis. Here, we report a binder of MtDTBS, cyclopentylacetic acid 2 (KD = 3.4 ± 0.4 mM), identified viain silico screening. X-ray crystallography showed that 2 binds in the 7,8-diaminopelargonic acid (DAPA) pocket of MtDTBS. Appending an acidic group to the para-position of the aromatic ring of the scaffold revealed compounds 4c and 4d as more potent binders, with KD = 19 ± 5 and 17 ± 1 μM, respectively. Further optimization identified tetrazole 7a as a particularly potent binder (KD = 57 ± 5 nM) and inhibitor (Ki = 5 ± 1 μM) of MtDTBS. Our findings highlight the first reported inhibitors of MtDTBS and serve as a platform for the further development of potent inhibitors and novel therapeutics for the treatment of tuberculosis.

中文翻译:

抑制结核分枝杆菌脱硫生物素合成酶 (MtDTBS):迈向下一代抗结核药物

结核分枝杆菌脱硫生物素合酶 ( Mt DTBS) 是一种重要的酶,参与结核病病原体结核分枝杆菌生物素的生物合成。在这里,我们报告了Mt DTBS 的粘合剂,环戊基乙酸2 ( K D = 3.4 ± 0.4 mM),通过计算机筛选鉴定。X 射线晶体学显示2结合在Mt DTBS的 7,8-二氨基壬酸 (DAPA) 口袋中。将酸性基团附加到支架芳环的对位显示化合物4c4d作为更有效的粘合剂,KD = 19 ± 5 和 17 ± 1 μM,分别。进一步优化确定四唑7a作为Mt DTBS的特别有效的粘合剂 ( K D = 57 ± 5 nM) 和抑制剂 ( K i = 5 ± 1 μM) 。我们的研究结果突出了第一个报道的Mt DTBS 抑制剂,并作为进一步开发用于治疗结核病的强效抑制剂和新疗法的平台。
更新日期:2021-11-19
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