A schematic representation of the multiscale networks needed to understand and predict drug action. Atomic interactions between drug and target lead to alterations in the function of cellular regulatory networks, which lead to changes in cellular- and tissue-level physiology, which, in turn, lead to alterations in organ-level networking, which lead to changes in whole-body functions. Networks at both the cellular/tissue level and organ level are needed to understand the mechanism of drug action and to predict therapeutic efficacy and adverse event probability. The drug-protein structures are taken from structures deposited in the Protein Data Bank (http://www.pdb.org) with PDB IDs of 3QC4 and 2Y03 (88, 89), with the authors’ permission.

An intracellular network to explain how drug-induced adverse events can propagate across scales of organization. Drug interaction with the target leads through the network to an alteration of channel activity, which leads to a change in duration of the myocyte action potential, which leads to prolongation of the QT interval as seen in the electrocardiogram. This can result in fatal arrhythmias such as torsades de pointes. This network explains how drugs used to treat very different pathophysiologies such as diarrhea (loperamide) and cancer (dasatanib) can lead to long QT syndrome as an adverse event. However, this network does not explain why only some people show drug-induced long QT syndrome and why only some patients with long QT syndrome develop fatal arrhythmias. Additional information on genomic status and tissue- and multiorgan-level networks may be needed to explain individual susceptibility. The drugs are shown in purple boxes. Red boxes are drug targets, green boxes are intermediate nodes, and blue boxes are channels responsible for the various phases of the myocyte action potential. The light blue box represents a node that is an intermediate and also a channel involved in myocyte action potential, and each brown box represents a node that is both an intermediate and also a drug target. Black arrows indicate edges that are either undirected or directed with an unknown effect type (inhibition or activation), red arrows indicate edges that are activating, and blue arrows indicate edges that are inhibitory. Abbreviation: I, current that arises from the functioning of the channel protein. Adapted from Berger et al. (15) with permission.