Data from multiple levels can not only facilitate human disease studies

Data from multiple levels can not only facilitate human disease studies, but also are beneficial to drug design, drug combination, and drug repurposing. Traditional drug discovery involves cell-based or target-focused screening of chemical compounds in a very expensive and lengthy process. By contrast, many drugs exert their effects by modulating biological pathways rather than individual targets. Large-scale genomes, transcriptomes, proteome, interactome data, and their integration with metabolomic data and computational modeling have now enabled a systems-level view of drug discovery and development 14. In Table 2, we provide a list of public resources that can support drug discovery by using systems-based approaches. Systems pharmacology aims to understand the actions and adverse effects of drugs by considering targets in the context of their biological pathways and regulatory networks 13, 15. Drug buy GW9662 combination therapy is a therapeutic intervention in which more than one drug therapy is administered to the patient. Mathematical modeling and clinical data show that some drug combination treatments have higher efficacy, fewer side effects, and less toxicity compared to single-drug treatment (rational polypharmacy) 89, 90. However, experimental screening of drug combinations is very costly and often only identifies a small number of synergistic combinations due to the large search space. Complex dependencies of drug-induced transcription profiles explored by mathematical models provide rich information for drug synergy identification. The DREAM consortium launched an open challenge to develop computational methods for ranking 91 compound pairs based on gene-expression profiles of human B cells treated with individual compounds at multiple time points and concentrations 91. Among the 32 methods the consortium assessed, four performed significantly better than random guessing, indicating that computational prediction of drug combination is possible. Zhao and colleagues reported a simple correlation-based strategy to reveal the synergistic effects of drug combinations by exploring the same data set 92. Jin and colleagues developed an enhanced Petri net model to recognize the synergistic effects of drug combinations from drug-treated microarray data 93. Rosiglitazone is an anti-diabetic drug that has been reported to increase the risk of cardiovascular complications, including myocardial infarction (MI). Zhao and colleagues searched for usage of a second drug in the FDA’s Adverse Event Reporting System (FAERS) that could mitigate the risk of rosiglitazone ssociated MI and found that the combination of rosiglitazone with exenatide significantly reduces rosiglitazone-associated MI. Using cell biological networks and theWiley Interdiscip Rev Syst Biol Med. Author manuscript; available in PMC 2016 July 01.Wang et al.Pagedata from a mouse model, they ML240MedChemExpress ML240 identified the regulatory mechanism underlying the mitigating effect of exenatide on rosiglitazone-associated MI 94. Owing to the high cost and lengthy time necessary for developing a new drug, drug repurposing, which aims to identify new indications of existing drugs, offers a promising alternative to de novo drug discovery. Many network-based methods have been developed for predicting drug repurposing. Two core concepts that support drug repurposing are drugtarget interactions and target-disease associations. As shown in Figure 5A, a single drug may have multiple targets, and identification of new.Data from multiple levels can not only facilitate human disease studies, but also are beneficial to drug design, drug combination, and drug repurposing. Traditional drug discovery involves cell-based or target-focused screening of chemical compounds in a very expensive and lengthy process. By contrast, many drugs exert their effects by modulating biological pathways rather than individual targets. Large-scale genomes, transcriptomes, proteome, interactome data, and their integration with metabolomic data and computational modeling have now enabled a systems-level view of drug discovery and development 14. In Table 2, we provide a list of public resources that can support drug discovery by using systems-based approaches. Systems pharmacology aims to understand the actions and adverse effects of drugs by considering targets in the context of their biological pathways and regulatory networks 13, 15. Drug combination therapy is a therapeutic intervention in which more than one drug therapy is administered to the patient. Mathematical modeling and clinical data show that some drug combination treatments have higher efficacy, fewer side effects, and less toxicity compared to single-drug treatment (rational polypharmacy) 89, 90. However, experimental screening of drug combinations is very costly and often only identifies a small number of synergistic combinations due to the large search space. Complex dependencies of drug-induced transcription profiles explored by mathematical models provide rich information for drug synergy identification. The DREAM consortium launched an open challenge to develop computational methods for ranking 91 compound pairs based on gene-expression profiles of human B cells treated with individual compounds at multiple time points and concentrations 91. Among the 32 methods the consortium assessed, four performed significantly better than random guessing, indicating that computational prediction of drug combination is possible. Zhao and colleagues reported a simple correlation-based strategy to reveal the synergistic effects of drug combinations by exploring the same data set 92. Jin and colleagues developed an enhanced Petri net model to recognize the synergistic effects of drug combinations from drug-treated microarray data 93. Rosiglitazone is an anti-diabetic drug that has been reported to increase the risk of cardiovascular complications, including myocardial infarction (MI). Zhao and colleagues searched for usage of a second drug in the FDA’s Adverse Event Reporting System (FAERS) that could mitigate the risk of rosiglitazone ssociated MI and found that the combination of rosiglitazone with exenatide significantly reduces rosiglitazone-associated MI. Using cell biological networks and theWiley Interdiscip Rev Syst Biol Med. Author manuscript; available in PMC 2016 July 01.Wang et al.Pagedata from a mouse model, they identified the regulatory mechanism underlying the mitigating effect of exenatide on rosiglitazone-associated MI 94. Owing to the high cost and lengthy time necessary for developing a new drug, drug repurposing, which aims to identify new indications of existing drugs, offers a promising alternative to de novo drug discovery. Many network-based methods have been developed for predicting drug repurposing. Two core concepts that support drug repurposing are drugtarget interactions and target-disease associations. As shown in Figure 5A, a single drug may have multiple targets, and identification of new.