Elucidating Compound Mechanism of Action by Network Perturbation Analysis.
Elucidating Compound Mechanism of Action by Network Perturbation Analysis.
复制标题
DOI：
10.1016/j.cell.2015.05.056
复制
发表时间：
2015-07-16
期刊：
影响因子：
64.5
通讯作者：
Califano A
中科院分区：
文献类型：
--
作者：
Woo JH;Shimoni Y;Yang WS;Subramaniam P;Iyer A;Nicoletti P;Rodríguez Martínez M;López G;Mattioli M;Realubit R;Karan C;Stockwell BR;Bansal M;Califano A
全基因组鉴定小分子化合物的作用机制（MoA）表征其靶点、效应器和活性调节剂，是一个高度相关但难以实现的目标，对评估化合物的功效和毒性具有重要意义。目前的方法是劳动密集型的，大多局限于阐明高亲和力结合靶蛋白。我们介绍了一种基于调控网络的方法，该方法通过评估其分子相互作用在复合扰动下的全局失调来阐明全基因组的MoA蛋白。细胞扰动谱分析鉴定了70%被测试化合物的已建立的MoA蛋白，并阐明了经实验验证的新蛋白。最后，未知的moa化合物分析显示抗癌药物阿特胺是谷胱甘肽过氧化物酶4脂质修复活性的抑制剂，实验证实了这一点，从而揭示了意想不到的与磺胺嘧啶活性的相似性。这表明调控网络分析可以为阐明小分子MoA和化合物相似性提供有价值的机制见解。
Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators, represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor-intensive and mostly limited to elucidating high-affinity binding target proteins. We introduce a regulatory network-based approach that elucidates genome-wide MoA proteins based on the assessment of the global dysregulation of their molecular interactions following compound perturbation. Analysis of cellular perturbation profiles identified established MoA proteins for 70% of the tested compounds and elucidated novel proteins that were experimentally validated. Finally, unknown-MoA compound analysis revealed altretamine, an anticancer drug, as an inhibitor of glutathione peroxidase 4 lipid repair activity, which was experimentally confirmed, thus revealing unexpected similarity to the activity of sulfasalazine. This suggests that regulatory network analysis can provide valuable mechanistic insight into the elucidation of small molecule MoA and compound similarity.