An Integrated System Biology Approach Yields Drug Repositioning Candidates for the Treatment of Heart Failure.

Identifying effective pharmacological treatments for heart failure (HF) patients remains critically important. Given that the development of drugs de novo is expensive and time consuming, drug repositioning has become an increasingly important branch. In the present study, we propose a two-step drug repositioning pipeline and investigate the novel therapeutic effects of existing drugs approved by the US Food and Drug Administration to discover potential therapeutic drugs for HF. In the first step, we compared the gene expression pattern of HF patients with drug-induced gene expression profiles to obtain preliminary candidates. In the second step, we performed a systems biology approach based on the known protein-protein interaction information and targets of drugs to narrow down preliminary candidates to obtain final candidates. Drug set enrichment analysis and literature search were applied to assess the performance of our repositioning approach. We also constructed a mode of action network for each candidate and performed pathway analysis for each candidate using genes contained in their mode of action network to uncover pathways that potentially reflect the mechanisms of candidates' therapeutic efficacy to HF. We discovered numerous preliminary candidates, some of which are used in clinical practice and supported by the literature. The final candidates contained nearly all of the preliminary candidates supported by previous studies. Drug set enrichment analysis and literature search support the validity of our repositioning approach. The mode of action network for each candidate not only displayed the underlying mechanisms of drug efficacy but also uncovered potential biomarkers and therapeutic targets for HF. Our two-step drug repositioning approach is efficient to find candidates with potential therapeutic efficiency to HF supported by the literature and might be of particular use in the discovery of novel effective pharmacological therapies for HF.