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We proposed a network-based systems pharmacology framework for comprehensive identification of new drug-target interactions on GPCRs.An integrative network analysis reveals that ADRA2A, ADRA2C and CHRM2 are associated with cardiovascular complications of the approved GPCR drugs.We experimentally validated that two network-predicted compounds (AM966 and Ki16425) showed high binding affinities on EP4.G protein-coupled receptors (GPCRs) are the largest super family with more than 800 membrane receptors. Currently, over 30% of the approved drugs target human GPCRs. However, only approximately 30 human GPCRs have been resolved three-dimensional crystal structures, which limits traditional structure-based drug discovery. Recent advances in network-based systems pharmacology approaches have demonstrated powerful strategies for identifying new targets of GPCR ligands. In this study, we proposed a network-based systems pharmacology framework for comprehensive identification of new drug-target interactions on GPCRs. Specifically, we reconstructed both global and local drug-target interaction networks for human GPCRs. Network analysis on the known drug-target networks showed rational strategies for designing new GPCR ligands and evaluating side effects of the approved GPCR drugs. We further built global and local network-based models for predicting new targets of the known GPCR ligands. The area under the receiver operating characteristic curve of more than 0.96 was obtained for the best network-based models in cross validation. In case studies, we identified that several network-predicted GPCR off-targets (e.g. ADRA2A, ADRA2C and CHRM2) were associated with cardiovascular complications (e.g. bradycardia and palpitations) of the approved GPCR drugs via an integrative analysis of drug-target and off-target-adverse drug event networks. Importantly, we experimentally validated that two newly predicted compounds, AM966 and Ki16425, showed high binding affinities on prostaglandin E2 receptor EP4 subtype with IC50 = 2.67 μM and 6.34 μM, respectively. In summary, this study offers powerful network-based tools for identifying polypharmacology of GPCR ligands in drug discovery and development.