<p>(A) Network-based influence between proteins with similar cavities (red) and ligands (blue), compared to the background influence of random proteins in the interactome (gray). The relative influence between targets in drug combinations is plotted in purple. The distributions include groups with up to five comparisons, and the maximum influence among all of the pairs in the group was taken as the representative; in other words, closest pairs were picked in those drug combinations that involved more than one target per drug, and in cavity and ligand comparisons that brought together more than two proteins. To correct for the group size, we defined a Z-score by sampling 10,000 random groups in the size range. The orange shape spans the area between the quartiles of drug combinations and the unbiased sampling of nodes. (B) Characteristics of protein pairs that could be targeted simultaneously (polypharmacology opportunities) or that are used in successful drug combinations. In the upper plot, proportion of pairs of protein belonging to the same topological module in the network (as defined by the overlapping cluster generator [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005522#pcbi.1005522.ref042" target="_blank">42</a>]); in the middle plot, pairs of proteins with the same biological process (BP) broad (‘slim’) term [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005522#pcbi.1005522.ref070" target="_blank">70</a>]; similarly, in the bottom plot, pairs of proteins with the same molecular function (MF). For simplicity, in the case of drug combinations, only those with one target per drug are included here.</p
