Identifying compound-target associations by combining bioactivity profile similarity search and public databases mining.
Identifying compound-target associations by combining bioactivity profile similarity search and public databases mining.
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DOI：
10.1021/ci200192v
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发表时间：
2011-09-26
影响因子：
5.6
通讯作者：
Bryant SH
中科院分区：
文献类型：
--
作者：
Cheng T;Li Q;Wang Y;Bryant SH
分子靶标鉴定对药物发现具有重要意义。在这里，我们开发了一种名为生物活性谱相似性搜索（BASS）的计算方法，通过使用公共数据库中相关化合物的已知靶标注释将靶标与小分子联系起来。为了对BASS进行评价，利用美国国家癌症研究所60人肿瘤细胞系抗癌药物筛选（NCI-60）中常用的4296种化合物构建了生物活性谱数据库。将每个化合物作为查询，在整个生物活性概况数据库中进行搜索，并将生物活性概况相似且大于0.75阈值的参考化合物视为查询的相邻化合物。潜在靶标随后通过使用查询化合物的已知靶标与鉴定的相邻化合物连接。大约45%的预测化合物-靶点关联被成功地回顾性验证，这表明BASS可能应用于识别未表征化合物的靶点，从而为乱交和多药理学的研究提供见解。此外，BASS还鉴定出了相当一部分具有相似生物活性的结构多样的化合物，这表明BASS在寻找针对感兴趣靶点的新分子方面具有“支架跳跃”的可行性。
Molecular target identification is of central importance to drug discovery. Here, we developed a computational approach, named bioactivity profile similarity search (BASS), for associating targets to small molecules by using the known target annotations of related compounds from public databases. To evaluate BASS, a bioactivity profile database was constructed using 4296 compounds that were commonly tested in the US National Cancer Institute 60 human tumor cell line anticancer drug screen (NCI-60). Each compound was used as a query to search against the entire bioactivity profile database, and reference compounds with similar bioactivity profiles above a threshold of 0.75 were considered as neighbor compounds of the query. Potential targets were subsequently linked to the identified neighbor compounds by using the known targets of the query compound. About 45% of the predicted compound-target associations were successfully verified retrospectively, suggesting the possible application of BASS in identifying the targets of uncharacterized compounds and thus providing insight into the study of promiscuity and polypharmacology. Furthermore, BASS identified a significant fraction of structurally diverse compounds with similar bioactivities, indicating its feasibility of “scaffold hopping” in searching novel molecules against the target of interest.