Identification of new classes of ricin toxin inhibitors by virtual screening
Identification of new classes of ricin toxin inhibitors by virtual screening
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DOI：
10.1016/j.toxicon.2010.05.009
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发表时间：
2010-09-15
期刊：
影响因子：
2.8
通讯作者：
Robertus, Jon D.
中科院分区：
文献类型：
--
作者：
Bai, Yan;Watt, Beth;Robertus, Jon D.
我们使用两个虚拟筛选程序ICM和GOLD，将近50，000个化合物对接到靶蛋白非A链（RTA）的两种构象中的每一种。有限的对照组表明，两个程序得分高的候选物可能比来自单个程序的列表中的候选物具有更高的配体概率。基于虚拟筛选，我们购买了306种化合物进行动力学测定。发现六种化合物对RTA具有适度但显著的抑制作用。它们也倾向于抑制滋贺毒素A链，具有大致相同的IC 50。这些化合物通常代表了新的化学平台，它们不像目前已知的抑制剂那样类似于RTA底物。这六种化合物也在基于细胞的测定中测试了它们保护细胞免受完整蓖麻毒素侵害的能力。两种化合物在这方面是有效的，显示出中等至强的非抑制作用，但也显示出一定的细胞毒性。RTA具有大的极性活性位点，是一种难以设计的药物靶点，预期其只能微弱地结合小分子。该方法发现这些新平台的能力是令人鼓舞的，并表明虚拟筛选有助于寻找rim和滋贺毒素抑制剂。(C)2010年由Elsevier Ltd.出版
We used two virtual screening programs, ICM and GOLD, to dock nearly 50,000 compounds Into each of two conformations of the target protein non A chain (RTA). A limited control set suggests that candidates scored highly by two programs may have a higher probability of being ligands than those in a list from a single program Based on the virtual screens, we purchased 306 compounds that were subjected to a kinetic assay Six compounds were found to give modest, but significant, inhibition of RTA They also tended to inhibit Shiga toxin A chain, with roughly the same IC50. The compounds generally represent novel chemical platforms that do not resemble RTA substrates, as currently known inhibitors do These six were also tested in a cell-based assay for their ability to protect cells from Intact ricin. Two compounds were effective in this regard, showing modest to strong non inhibition, but also showing some cytotoxicity. RTA, with its large, polar active site is a difficult drug design target which is expected to bind small molecules only weakly. The ability of the method to find these novel platforms is encouraging and suggests virtual screening can contribute to the search for rim and Shiga toxin inhibitors. (C) 2010 Published by Elsevier Ltd.