Classification of the synergisms for the human metabolic network. Top panel: Each leaf of the tree represents a multidrugsolution that we have found. The layout of the graph is obtained through thesame method used for phylogenetic trees (a distance tree, see text) andmanifestly shows the clustering of these synergisms; the six clearly visibleclasses have been labeled with letters (from “A” to“F”). Names of the pathways mainly affected by each classare reported near the clusters. Bottom panel: This network of drugsrepresents a detailed characterization of the classes of synergisms. Each drugis indicated by a circle (whose radius is proportional to the number of itsdirect targets; drugs are labeled with numbers according to Additional file1: Table S1). Each synergism is drawn as a coloredline which connects the drugs involved (each synergism has its own color andthe line thickness is proportional to the number of stopped reactions). Even inthis more detailed representation, the six classes are still visible. Somesubclasses can also be identified: drug pairs (7, 62) and (7, 65) in class Aand drug pairs (42, 58) and (51, 58) in class E (indicated with broken lines)exploit part of the synergism of the entire class; indeed these 4 pairs are theisolated leaves in the corresponding clusters in the top panel. Note the roleof drugs 7, 22 and 50 in bridging classes A-C, A-Band E-F. Details of the metabolic functions to which theseclasses of synergisms correspond are given in Figure 3.