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本文引用的文献

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AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.AutoDock Vina：通过新的评分函数、高效优化和多线程改进对接的速度和准确性。
J Comput Chem. 2010 Jan 30;31(2):455-61. doi: 10.1002/jcc.21334.
2
Discovery, synthesis, and biological evaluation of piperidinol analogs with anti-tuberculosis activity.具有抗结核活性的哌啶醇类似物的发现、合成及生物学评价
Bioorg Med Chem. 2009 May 15;17(10):3588-94. doi: 10.1016/j.bmc.2009.04.005. Epub 2009 Apr 9.
3
Very fast prediction and rationalization of pKa values for protein-ligand complexes.蛋白质-配体复合物pKa值的快速预测与合理化分析
Proteins. 2008 Nov 15;73(3):765-83. doi: 10.1002/prot.22102.
4
Targeting the formation of the cell wall core of M. tuberculosis.针对结核分枝杆菌细胞壁核心的形成。
Infect Disord Drug Targets. 2007 Jun;7(2):182-202. doi: 10.2174/187152607781001808.
5
Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa.广泛耐药结核病是南非农村地区结核病与艾滋病毒合并感染患者的死因之一。
Lancet. 2006 Nov 4;368(9547):1575-80. doi: 10.1016/S0140-6736(06)69573-1.
6
XDR tuberculosis: an indicator of public-health negligence.广泛耐药结核病：公共卫生疏忽的一个指标。
Lancet. 2006 Nov 4;368(9547):1554-6. doi: 10.1016/S0140-6736(06)69575-5.
7
RmlC, a C3' and C5' carbohydrate epimerase, appears to operate via an intermediate with an unusual twist boat conformation.RmlC是一种C3'和C5'碳水化合物差向异构酶，它似乎通过一种具有不寻常扭曲船式构象的中间体起作用。
J Mol Biol. 2007 Jan 5;365(1):146-59. doi: 10.1016/j.jmb.2006.09.063. Epub 2006 Sep 29.
8
Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes.超高精度滑动：结合蛋白质-配体复合物疏水包封模型的对接与评分
J Med Chem. 2006 Oct 19;49(21):6177-96. doi: 10.1021/jm051256o.
9
rmlB and rmlC genes are essential for growth of mycobacteria.rmlB和rmlC基因对分枝杆菌的生长至关重要。
Biochem Biophys Res Commun. 2006 Mar 31;342(1):170-8. doi: 10.1016/j.bbrc.2006.01.130. Epub 2006 Feb 3.
10
Evaluation of enzyme inhibitors in drug discovery. A guide for medicinal chemists and pharmacologists.药物研发中酶抑制剂的评估。给药物化学家与药理学家的指南。
Methods Biochem Anal. 2005;46:1-265.

鉴定三嗪并吲唑并苯并咪唑酮类化合物为结核分枝杆菌酶 TDP-6-脱氧-d-木糖-4-己酮糖-4-差向异构酶（RmlC）的纳摩尔抑制剂。

Identification of triazinoindol-benzimidazolones as nanomolar inhibitors of the Mycobacterium tuberculosis enzyme TDP-6-deoxy-d-xylo-4-hexopyranosid-4-ulose 3,5-epimerase (RmlC).

机构信息

Penn Center for Molecular Discovery, Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, 1024 Vagelos Research Laboratories, University of Pennsylvania, Philadelphia, PA 19104, USA.

出版信息

Bioorg Med Chem. 2010 Jan 15;18(2):896-908. doi: 10.1016/j.bmc.2009.11.033. Epub 2009 Nov 20.

DOI:10.1016/j.bmc.2009.11.033
PMID:19969466
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2818544/
Abstract

High-throughput screening of 201,368 compounds revealed that 1-(3-(5-ethyl-5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)propyl)-1H-benzo[d]imidazol-2(3H)-one (SID 7975595) inhibited RmlC a TB cell wall biosynthetic enzyme. SID 7975595 acts as a competitive inhibitor of the enzyme's substrate and inhibits RmlC as a fast-on rate, fully reversible inhibitor. An analog of SID 7975595 had a K(i) of 62nM. Computer modeling showed that the binding of the tethered two-ringed system into the active site occurred at the thymidine binding region for one ring system and the sugar region for the other ring system.

摘要

高通量筛选 201368 种化合物显示，1-(3-(5-乙基-5H-[1,2,4]三嗪并[5,6-b]吲哚-3-基硫基)丙基)-1H-苯并[d]咪唑-2(3H)-酮（SID 7975595）抑制了 RmlC aTB 细胞壁生物合成酶。SID 7975595 作为该酶底物的竞争性抑制剂，以快速结合率和完全可逆的方式抑制 RmlC。SID 7975595 的类似物的 K(i)为 62nM。计算机建模表明，连接的双环系统与活性位点的结合发生在一个环系统的胸腺嘧啶结合区域和另一个环系统的糖区域。