Suthagar Kajitha, Jiao Wanting, Munier-Lehmann Hélène, Fairbanks Antony J
Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, 8140, New Zealand.
Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, 8140, New Zealand; Ferrier Research Institute, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.
Carbohydr Res. 2018 Mar 2;457:32-40. doi: 10.1016/j.carres.2018.01.001. Epub 2018 Jan 11.
The recently discovered enzyme Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), which catalyses the phosphorylation of deoxythymidine monophosphate (dTMP) to give deoxythymidine diphosphate (dTDP), is indispensable for the growth and survival of M. tuberculosis as it plays an essential role in DNA synthesis. Inhibition of TMPKmt is an attractive avenue for the development of novel anti-tuberculosis agents. Based on the premise that sulfamide may be a suitable isostere of phosphate, deoxythymidine analogues comprising various substituted sulfamides at C5' were modelled in silico into the active site of TMPKmt (PDB accession code: 1N5K) using induced-fit docking methods. A selection of modelled compounds was synthesized, and their activity as inhibitors of TMPKmt was evaluated. Three compounds showed competitive inhibition of TMPKmt in the micromolar range (10-50 μM). Compounds were tested in vitro for anti-mycobacterial activity against M. smegmatis: three compounds showed weak anti-mycobacterial activity (MIC 250 μg/mL).
最近发现的结核分枝杆菌胸苷单磷酸激酶（TMPKmt）可催化脱氧胸苷单磷酸（dTMP）磷酸化生成脱氧胸苷二磷酸（dTDP），由于其在DNA合成中起关键作用，所以对结核分枝杆菌的生长和存活至关重要。抑制TMPKmt是开发新型抗结核药物的一个有吸引力的途径。基于磺酰胺可能是磷酸合适电子等排体的前提，利用诱导契合对接方法，在计算机上将C5'位含有各种取代磺酰胺的脱氧胸苷类似物模拟到TMPKmt的活性位点（蛋白质数据库登录号：1N5K）。合成了一系列模拟化合物，并评估了它们作为TMPKmt抑制剂的活性。三种化合物在微摩尔范围内（10 - 50 μM）对TMPKmt表现出竞争性抑制作用。对这些化合物进行了体外抗耻垢分枝杆菌的抗分枝杆菌活性测试：三种化合物表现出较弱的抗分枝杆菌活性（最低抑菌浓度为250 μg/mL）。
