上海科技大学知识管理系统

Profiling drug-protein interactions is criticalfor understandinga drug's mechanism of action and predicting the possible adverseside effects. However, to comprehensively profile drug-proteininteractions remains a challenge. To address this issue, we proposeda strategy that integrates multiple mass spectrometry-based omicsanalysis to provided global drug-protein interactions, includingphysical interactions and functional interactions, with rapamycin(Rap) as a model. Chemoproteomics profiling reveals 47 Rap bindingproteins including the known target protein FKBP12 with high confidence.Gen Ontology enrichment analysis suggested that the Rap binding proteinsare implicated in several important cellular processes, such as DNAreplication, immunity, autophagy, programmed cell death, aging, transcriptionmodulation, vesicle-mediated transport, membrane organization, andcarbohydrate and nucleobase metabolic processes. The phosphoproteomicsprofiling revealed 255 down-regulated and 150 up-regulated phosphoproteinsresponding to Rap stimulation; they mainly involve the PI3K-Akt-mTORC1signaling axis. Untargeted metabolomic profiling revealed 22 down-regulatedmetabolites and 75 up-regulated metabolites responding to Rap stimulation;they are mainly associated with the synthesis processes of pyrimidineand purine. The integrative multiomics data analysis provides deepinsight into the drug-protein interactions and reveals Rap'scomplicated mechanism of action.