Drug2ways: Reasoning over causal paths in biological networks for drug discovery
Fig 1
Schematic illustration of causal reasoning by drug2ways over simplified networks.
a) Prototypic network used by drug2ways for drug discovery. The network contains causal relations between three modalities (i.e., drugs, proteins, and indications/phenotypes). Here, singular paths from three drugs to an indication as well as associated phenotypes are shown, though a single drug may contain multiple paths to a given indication/phenotype. Drug2ways reasons over all possible paths in a network between a drug and an indication/phenotype to predict the relative effect of each drug. In the example, we want to investigate whether one of the three drugs depicted inhibits an indication and its two phenotypes. While all three drugs target the disease, two of the three (i.e., drug A and C) fail to produce the desired effects (i.e., inhibition of the indication of interest and its two associated phenotypes). By reasoning over all the paths between the drug and the three target nodes of interest (i.e., indication and its phenotypes), drug2ways predicts that drug B could be a promising candidate as the majority of the paths would result in their inhibition, and thus produce a therapeutic effect. Similarly, drug2ways can also be used to evaluate the effect of a drug on a single indication/phenotype or to assess the effect of drug combinations. b) Example network containing all paths between a given drug and an indication. c) All possible paths between the drug and indication in (b). The drug2ways algorithm incorporates two variants, namely all paths and simple paths, enabling users to account for or ignore feedback loops (i.e., cycles), respectively. We distinguish between different paths based on the maximum number of allowable edges from a drug X to an indication Y (i.e., lmax parameter). For instance, the shortest path between the drug and the indication has an lmax of 3 while an lmax of 6 will capture this and four additional simple paths, two of length 4 and a further two of length 6. Using the all paths version of the algorithm, an additional cyclic path of length 6 is also captured.