Robust Target Identification for Drug Discovery

详细信息    查看全文

• 作者：Elling W. Jacobsen ^{jacobsen@kth.se" class="auth_mail" title="E-mail the corresponding author} ; Torbjö ; rn E.M. Nordling ^{tn@kth.se" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Systems biology ; systems medicine ; target identification ; network inference ; robust regression ; gene regulatory networks ; drug discovery
• 刊名：IFAC-PapersOnLine
• 出版年：2016
• 出版时间：2016
• 年：2016
• 卷：49
• 期：7
• 页码：815-820
• 全文大小：454 K

文摘

A key step in the development of new pharmaceutical drugs is that of identifying direct targets of the bioactive compounds, and distinguishing these from all other gene products that respond indirectly to the drug targets. Currently dominating approaches to this problem are based on often time consuming and costly experimental methods aimed at locating physical bindings of the corresponding small molecule to proteins or DNA sequences. In this paper we consider target identification based on time-series expression data of the corresponding gene regulatory network, using perturbation with the active compound only. As we show, the problem of identifying the direct targets can then be cast as a linear regression problem and, in principle, be accomplished with a number of samples equal to the number of involved genes and bioactive compounds. However, the regression matrix will typically be highly ill-conditioned and the target identification therefore prone even to small measurement uncertainties. In order to provide a label of confidence for the target identification, we consider conditions that can be used to quantify the robustness of the identification of individual drug targets with respect to uncertainty in the expression data. For this purpose, we cast the uncertain regression problem as a robust rank problem and employ SVD or the structured singular value to compute the robust rank. The proposed method is illustrated by application to a small scale gene regulatory network synthesised in yeast to serve as a benchmark problem in network inference.