Types of network studies in systems pharmacology. Network studies in systems pharmacology can be grouped into three broad categories. (A) Global drug network studies that incorporate information about many types of drugs and biological datasets such as protein–protein interaction data can generate network properties of drug targets. These properties give information about historical drug development trends and can suggest properties of what makes a target druggable. (B) Disease specific network studies use information about a specific disease to identify potential new drug targets and therapeutic strategies. (C) Studies that integrate information about specific diseases and drugs can identify new indications for drugs, unknown targets of drugs, and other potentially interesting properties of the drugs.

Different relationships between nodes in networks used in systems pharmacology. In systems pharmacology, networks can be used to understand the relationship between drugs, their targets and diseases. Nodes can be genes, proteins, small molecules, drugs, diseases or any other biological entity capable of interacting in the system of interactions being modeled. Edges can be directed or undirected, weighted or not weighted and can represent direct physical interactions, activation, inhibition, coregulation or any other relationship between the nodes. Using networks centered on dasatinib, a tyrosine kinase inhibitor used to treat chronic mylogenous leukemia as an example, depicted above are small sub-networks demonstrating different types of nodes, represented by shaded shapes and edges, represented by lines. (A) Nodes are proteins connected by physical interactions found in literature. Diamond shaped nodes are annotated as targets of dasatinib and interacting proteins shown as octagons physically interact with at least two of the drug targets. (B) Oval nodes are drugs connected by shared targets within two steps of dasatinib, shown in a triangle. Dasatinib connects directly to other tyrosine kinase inhibitors. Imatinib also connects to clusters of drugs which interact with the ABCB1 and ABCG2 drug efflux pumps. (C) Oval nodes are drugs connected by sharing a therapeutic indication as described by the Anatomical Therapeutic Chemcial Classification System (ATC) third level codes. Within two steps of dasatinib shown in a triangle, the network forms three connected clusters. The cluster on the left of anti-neoplastic agents is connected to the cluster of anti-inflammatory agents on the right through celecoxib which has both indications. Both these clusters have connections to drugs above them in which are topical acne treatments. Drug targets and indication codes were taken from Drugbank (Wishart et al., 2008) and the protein interaction network was taken from Genes2Networks (Berger et al., 2007). These examples demonstrate different ways that one can study different aspects of the same drug using different types of networks.

Changing views of drug actions. Network studies in systems pharmacology are changing the way we think about the actions of drugs. (A) The classic view of drug action has a drug that interacts with a therapeutic target which transduces its signal through its effector pathway to mediate a therapeutic effect and certain side effects. Additional off-targets can mediate effects through distinct effector pathways to lead to other side effects and other adverse events. (B) In a systems pharmacology view of drug action, a drug interacts with multiple primary and secondary targets. These targets exist within a complex network which can mediate the response to the drugs leading to both the therapeutic and adverse effects.