A strategy based on protein-protein interface motifs may help in identifying drug off-targets.
A strategy based on protein-protein interface motifs may help in identifying drug off-targets.
复制标题
DOI：
10.1021/ci300072q
复制
发表时间：
2012-08-27
影响因子：
5.6
通讯作者：
Gursoy A
中科院分区：
文献类型：
--
作者：
Engin HB;Keskin O;Nussinov R;Gursoy A
网络越来越多地用于在系统一级研究药物的影响。从算法的角度来看，药物可以“攻击”蛋白质-蛋白质相互作用网络的节点或边缘。在这项工作中，我们提出了一种新的基于蛋白质-蛋白质界面的网络策略“接口攻击”。类似的界面结构可以发生在不相关的蛋白质之间。因此，原则上，一种药物与一种药物结合，就有一定的可能性与其他药物结合。接口攻击策略同时从网络中删除所有由类似接口主题组成的交互。这种策略受到网络药理学的启发，可以推断潜在的脱靶。我们介绍了一个网络模型，我们称之为“蛋白质界面和相互作用网络（P2IN）”，它是蛋白质-蛋白质界面结构和蛋白质相互作用网络的集成。这种基于界面的网络组织澄清了哪些蛋白质对具有结构相似的界面，以及哪些蛋白质可能竞争结合相同的表面区域。我们构建了p53信号网络的P2IN，并进行了网络鲁棒性分析。我们表明：(1)“击中”频繁的接口（分布在网络周围的一组边缘）可能与消除高度蛋白质（集线器节点）一样具有破坏性；(2)频繁接口并不总是网络拓扑中的关键元素；(3)界面攻击比单一蛋白攻击更能揭示系统的功能变化。在脱靶检测案例研究中，我们发现阻断CDK6和CDKN2D界面的药物也可能影响CDK4和CDKN2D之间的相互作用。
Networks are increasingly used to study the impact of drugs at the systems level. From the algorithmic standpoint, a drug can ‘attack’ nodes or edges of a protein-protein interaction network. In this work, we propose a new network strategy, “The Interface Attack”, based on protein-protein interfaces. Similar interface architectures can occur between unrelated proteins. Consequently, in principle, a drug that binds to one has a certain probability of binding others. The interface attack strategy simultaneously removes from the network all interactions that consist of similar interface motifs. This strategy is inspired by network pharmacology and allows inferring potential off-targets. We introduce a network model which we call “Protein Interface and Interaction Network (P2IN)”, which is the integration of protein-protein interface structures and protein interaction networks. This interface-based network organization clarifies which protein pairs have structurally similar interfaces, and which proteins may compete to bind the same surface region. We built the P2IN of p53 signaling network and performed network robustness analysis. We show that (1) ‘hitting’ frequent interfaces (a set of edges distributed around the network) might be as destructive as eleminating high degree proteins (hub nodes); (2) frequent interfaces are not always topologically critical elements in the network; and (3) interface attack may reveal functional changes in the system better than attack of single proteins. In the off-target detection case study, we found that drugs blocking the interface between CDK6 and CDKN2D may also affect the interaction between CDK4 and CDKN2D.
登录
查看更多内容
DOI：
10.1126/science.1162327
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badis G;Berger MF;Philippakis AA;Talukder S;Gehrke AR;Jaeger SA;Chan ET;Metzler G;Vedenko A;Chen X;Kuznetsov H;Wang CF;Coburn D;Newburger DE;Morris Q;Hughes TR;Bulyk ML
通讯作者：
Bulyk ML
影响因子：
11.2
作者：
Baughn, Linda B.;Di Liberto, Maurizio;Chen-Kiang, Selina
通讯作者：
Chen-Kiang, Selina
影响因子：
3.5
作者：
Dartnell, L;Simeonidis, E;Papageorgiou, LG
通讯作者：
Papageorgiou, LG
影响因子：
14.5
作者：
Bloom, J;Pagano, M
通讯作者：
Pagano, M
影响因子：
56.9
作者：
Campillos, Monica;Kuhn, Michael;Bork, Peer
通讯作者：
Bork, Peer