Design, synthesis, and X-ray analysis of a glycoconjugate bound to Mycobacterium tuberculosis antigen 85C.
Design, synthesis, and X-ray analysis of a glycoconjugate bound to Mycobacterium tuberculosis antigen 85C.
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与结核分枝杆菌抗原 85C 结合的糖复合物的设计、合成和 X 射线分析。
DOI：
10.1021/bc3004342
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发表时间：
2012-12-19
影响因子：
4.7
通讯作者：
Sucheck, Steven J.
中科院分区：
文献类型：
--
作者：
Ibrahim, Diaa A.;Boucau, Julie;Lajiness, Daniel H.;Veleti, Sri Kumar;Trabbic, Kevin R.;Adams, Samuel S.;Ronning, Donald R.;Sucheck, Steven J.
结核病(TB)是一种全球健康威胁，据估计，每年新增近50万例耐多药结核病病例，因此迫切需要新药。目前的一些抗分枝杆菌药物通过干扰分枝杆菌半乳糖(MAG)关键成分的生物合成来发挥作用。根据这一观察结果，参与MAG合成的其他酶也应该作为抗分枝杆菌药物开发的靶点。一个潜在的靶点是抗原85(Ag85)复合体，这是一个真菌转移酶家族，负责将真菌酸从海藻糖单菌酯(TMM)转移到阿拉伯半乳糖。使用Glide将虚拟的硫代苯基-阿比诺苷结合物对接到抗原Ag85C(PDB代码：1va5)上。通过Gewald合成，然后连接到5-硫代阿拉伯呋喃糖苷，合成了具有良好对接分数的化合物。用4-甲基伞形花环丁酸酯荧光法测定了所得的硫代苯基-阿拉伯硫代呋喃糖苷对霉基转移酶活性的抑制作用。结合物的KI值为18.2~71.0µM，最强的缓蚀剂被浸泡在结核杆菌抗原85C的晶体中，并确定了其结构。X-射线结构表明，与噻吩基结合在酶活性中心内的化合物位于TMM的α链结合部位，而阿拉伯氟尿苷部分位于已知的碳水化合物结合部位，与Ag85B-海藻糖晶体结构相同。出乎意料的是，在阿拉伯呋喃糖苷和活性部位的碳水化合物结合部位之间没有形成特定的氢键作用，这表明阿拉伯糖苷在该结构中的结合是由阿拉伯糖基和碳水化合物结合部位之间的形状互补驱动的。
Tuberculosis (TB) is a global health threat with nearly 500,000 new cases of multidrug-resistance TB estimated to occur every year, so new drugs are desperately needed. A number of current antimycobacterial drugs work by interfering with the biosynthesis of key components of the mycolylarabinogalactan (mAG). In light of this observation, other enzymes involved in the synthesis of the mAG should also serve as targets for antimycobacterial drug development. One potential target is the Antigen 85 (Ag85) complex, a family of mycolyltransferases that are responsible for the transfer of mycolic acids from trehalose monomycolate (TMM) to the arabinogalactan. Virtual thiophenyl-arbinoside conjugates were docked to antigen Ag85C (PDB code: 1va5) using Glide. Compounds with good docking scores were synthesized by a Gewald synthesis followed by linking to 5-thioarabinofuranosides. The resulting thiophenyl-thioarabinofuranosides were assayed for inhibition of mycoyltransferase activity using a 4-methylumbelliferyl butyrate fluorescence assay. The conjugates showed Ki values ranging from 18.2 to 71.0 µM. The most potent inhibitor was soaked into crystals of Mycobacterium tuberculosis antigen 85C and the structure of the complex determined. The X-ray structure shows the compound bound within the active site of the enzyme with the thiophene moiety is positioned in the putative α-chain binding site of TMM and the arabinofuranoside moiety within the known carbohydrate-binding site as exhibited for the Ag85B-trehalose crystal structure. Unexpectedly, no specific hydrogen bonding interactions are being formed between the arabinofuranoside and the carbohydrate-binding site of the active site suggesting that the binding of the arabinoside within this structure is driven by shape complementarily between the arabinosyl moiety and the carbohydrate binding site.
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影响因子：
2.9
作者：
Jacobson, MP;Pincus, DL;Friesner, RA
通讯作者：
Friesner, RA
DOI：
10.1002/cber.19660990116
发表时间：
1966-01-01
期刊：
CHEMISCHE BERICHTE-RECUEIL
影响因子：
--
作者：
GEWALD, K;SCHINKE, E;BOTTCHER, H
通讯作者：
BOTTCHER, H
影响因子：
6.7
作者：
Gobec, Stanislav;Plantan, Ivan;Kikelj, Danijel
通讯作者：
Kikelj, Danijel
DOI：
10.1107/s0907444902016657
发表时间：
2002-11-01
影响因子：
2.2
作者：
Adams, PD;Grosse-Kunstleve, RW;Terwilliger, TC
通讯作者：
Terwilliger, TC
影响因子：
2.1
作者：
Bilokin, YV;Vasylyev, MV;Chernykh, VP
通讯作者：
Chernykh, VP