Drug target identification using side-effect similarity
Drug target identification using side-effect similarity
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DOI：
10.1126/science.1158140
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发表时间：
2008-07-11
期刊：
影响因子：
56.9
通讯作者：
Bork, Peer
中科院分区：
文献类型：
--
作者：
Campillos, Monica;Kuhn, Michael;Bork, Peer
到目前为止，药物的靶标是根据分子或细胞特征来预测的，例如，通过利用不同细胞系之间化学结构或活性的相似性。我们使用表型副作用相似性来推断两种药物是否有共同的靶标。通过对746种已上市药物的研究，发现了1018种由副作用驱动的药物-药物关系网络，其中261种是由不同治疗适应症的化学成分不同的药物形成的。我们通过实验测试了其中20种意想不到的药物-药物关系，并通过体外结合试验验证了13种隐含的药物-靶标关系，其中11种显示抑制常数小于10微摩尔。其中9种在细胞分析中进行了测试和确认，证明了利用表型信息推断分子相互作用的可行性，并暗示了上市药物的新用途。
Targets for drugs have so far been predicted on the basis of molecular or cellular features, for example, by exploiting similarity in chemical structure or in activity across cell lines. We used phenotypic side- effect similarities to infer whether two drugs share a target. Applied to 746 marketed drugs, a network of 1018 side effect- driven drug- drug relations became apparent, 261 of which are formed by chemically dissimilar drugs from different therapeutic indications. We experimentally tested 20 of these unexpected drug- drug relations and validated 13 implied drug- target relations by in vitro binding assays, of which 11 reveal inhibition constants equal to less than 10 micromolar. Nine of these were tested and confirmed in cell assays, documenting the feasibility of using phenotypic information to infer molecular interactions and hinting at new uses of marketed drugs.