Networks from drug–drug surfaces

Mol Syst Biol. 3: 85 Multi‐drug combinations are vital in modern medicine (Keith et al , 2005; Fitzgerald et al , 2006). Such drug combinations can also be used to probe the relationships between proteins in a network, and progress towards using drug interactions to infer network connectivity has been made in recent years. A current study by Lehar et al (2007) takes this effort a large step further by developing tools to use the entire data in a drug–drug interaction dose–response surface to give useful information on the networks in which the drug targets are embedded. Classically, combinations of perturbations—drugs or mutations—have been categorized into one of three interaction types: additive, synergistic, or antagonistic (Bliss, 1939; Loewe, 1953; Hartman et al , 2001). The expected null interaction is called additive, although exactly how this should be defined has been a subject of some controversy (Bliss, 1939; Loewe, 1953; Greco et al , 1995). Synergy occurs when the combination of two perturbations has an effect greater than expected from the individual effects of the single perturbations. Antagonism describes a combination with less than expected effect. These classifications have proved powerful in dissecting the modularity and connectivity of the underlying biological networks (Tong et al , 2001; Schuldiner et al , 2005; Segre et al , 2005; Yeh et al …