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.
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。
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