An integrated strategy for identifying new targets and inferring the mechanism of action: taking rhein as an example

BACKGROUND: Target identification is necessary for the comprehensive inference of the mechanism of action of a compound. The application of computational methods to predict the targets of bioactive compounds saves cost and time in drug research and development. Therefore, we designed an integrated strategy consisting of ligand-protein docking, network analysis, enrichment analysis, and an experimental surface plasmon resonance (SPR) method to identify and validate new targets, and then used enriched pathways to elucidate the underlying pharmacological mechanisms. Here, we used rhein, a compound with various pharmacological activities, as an example to find some of its previously unknown targets and to determine its pharmacological activity. RESULTS: A total of nine candidate targets were discovered, including LCK, HSP90AA1, RAB5A, EGFR, CDK2, CDK6, GSK3B, p38, and JNK. LCK was confirmed through SPR experiments, and HSP90AA1, EGFR, CDK6, p38, and JNK were validated through previous reports. Rhein network regulations are complex and interconnected. The therapeutic effect of rhein is the synergistic and comprehensive result of this vast and complex network, and the perturbation of multiple targets gives rhein its various pharmacological activities. CONCLUSIONS: This study provided a new integrated strategy to identify new targets of bioactive compounds and reveal their molecular mechanisms of action. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12859-018-2346-4) contains supplementary material, which is available to authorized users.