Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland.
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Molecules. 2020 Jun 23;25(12):2894. doi: 10.3390/molecules25122894.
With the aim to identify novel inhibitors of parasitic nematode thymidylate synthase (TS), we screened in silico an in-house library of natural compounds, taking advantage of a model of nematode TS three-dimensional (3D) structure and choosing candidate compounds potentially capable of enzyme binding/inhibition. Selected compounds were tested as (i) inhibitors of the reaction catalyzed by TSs of different species, (ii) agents toxic to a nematode parasite model ( grown in vitro), (iii) inhibitors of normal human cell growth, and (iv) antitumor agents affecting human tumor cells grown in vitro. The results pointed to alvaxanthone as a relatively strong TS inhibitor that causes population growth reduction with nematocidal potency similar to the anthelmintic drug mebendazole. Alvaxanthone also demonstrated an antiproliferative effect in tumor cells, associated with a selective toxicity against mitochondria observed in cancer cells compared to normal cells.
为了鉴定寄生性线虫胸苷酸合成酶（TS）的新型抑制剂，我们利用线虫 TS 三维（3D）结构模型，对内部天然化合物库进行了计算机筛选，选择了可能具有酶结合/抑制作用的候选化合物。所选化合物被测试为：（i）不同物种 TS 催化反应的抑制剂；（ii）体外培养的线虫寄生虫模型的毒性剂；（iii）正常人细胞生长抑制剂；（iv）影响体外生长的人肿瘤细胞的抗肿瘤剂。结果表明，alvaxanthone 是一种相对较强的 TS 抑制剂，其对寄生虫种群的生长抑制作用类似于驱虫药物苯并咪唑。Alvaxanthone 还在肿瘤细胞中表现出抗增殖作用，与正常细胞相比，在癌细胞中观察到线粒体的选择性毒性。
