Pandey Preeti, Verma Vijay, Gautam Gunjan, Kumari Nilima, Dhar Suman Kumar, Gourinath Samudrala
School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
Department of Bioscience and Biotechnology, Banasthali University, Jaipur, India.
FEBS Lett. 2017 Aug;591(15):2311-2322. doi: 10.1002/1873-3468.12734. Epub 2017 Jul 26.
The β-clamp is the processivity-promoting factor for most of the enzymes in prokaryotic DNA replication; hence, it is a crucial drug target. In the present study, we investigated the β-clamp from Helicobacter pylori, aiming to seek potential drug molecules against this gastric-cancer-causing bacterium. An in silico screening of Food and Drug Administration (FDA) approved drugs against the H. pylori β-clamp, followed by its in vitro inhibition using a surface competition approach, yielded the drug diflunisal as a positive initial hit. Diflunisal inhibits the growth of H. pylori in the micromolar range. We determined the structure of diflunisal in complex with the β-clamp to show that the drug binds at subsite I, which is a protein-protein interaction site. Successful identification of FDA-approved molecules against H. pylori may lead to better and faster drug development.
β夹子是原核生物DNA复制中大多数酶的持续性促进因子；因此，它是一个关键的药物靶点。在本研究中，我们研究了幽门螺杆菌的β夹子，旨在寻找针对这种导致胃癌的细菌的潜在药物分子。对美国食品药品监督管理局（FDA）批准的药物针对幽门螺杆菌β夹子进行计算机模拟筛选，随后采用表面竞争方法对其进行体外抑制，结果显示双氟尼酸作为初步阳性命中药物。双氟尼酸在微摩尔范围内抑制幽门螺杆菌的生长。我们确定了双氟尼酸与β夹子复合物的结构，以表明该药物结合在亚位点I，这是一个蛋白质-蛋白质相互作用位点。成功鉴定出针对幽门螺杆菌的FDA批准分子可能会带来更好、更快的药物开发。
