Fig. 4: Drug target discovery via Steiner tree analysis to identify putative molecular pathways linking differentially expressed genes in SARS-CoV-2 infection and aging.

a The general procedure takes as input a list of genes of interest (terminal nodes) with prizes indicating their respective importance, a protein–protein interaction (PPI) network with edge cost/confidence information (e.g., from IRefIndex v14⁴², edge cost shown by blue shading), and a list of drugs of interest along with their protein targets and available activity constants (e.g., from DrugCentral^44,45, activity constants shown by green shading). In this study, we consider 181 terminal nodes, shown as a purple circle in the Venn diagram (of which 162 are present in the PPI network) corresponding to genes differentially expressed in SARS-CoV-2 infection (red circle) and aging (blue circle) from Fig. 2 that are either upregulated in both SARS-CoV-2 infection and aging or downregulated in both SARS-CoV-2 infection and aging. The prize of a terminal node equals the absolute value of its \({\mathrm{log}\,}_{2}\)-fold change in SARS-CoV-2-infected A549-ACE2 cells versus normal A549-ACE2 cells (shown in purple shading) based on the data from ref. ²³. Terminals and PPI data are processed using OmicsIntegrator2³⁰ to output the disease interactome, i.e., the subnetwork induced by a Steiner tree, with drug targets indicated by green diamonds and terminal nodes colored according to their prizes. Gray nodes represent Steiner nodes. b Interactome obtained using this procedure. Proteins are grouped by general function (colored boxes in the background) and marked with a cross if they are known to interact with SARS-CoV-2 proteins based on data from⁶. c 2-Nearest-neighborhoods of nodes of interest (denoted by a red hexagon) in the interactome. Proteins known to interact with SARS-CoV-2 are denoted by blue squares, drug targets are denoted as green diamonds, terminal nodes are colored according to their \({\mathrm{log}\,}_{2}\)-fold change in SARS-CoV-2-infected A549-ACE2 cells versus normal A549-ACE2 cells, Steiner nodes appear in gray. Edges are colored according to edge confidence, which is thresholded to improve readability (see “Methods”). d Table of drug targets and corresponding drugs in the interactome. Selected drugs are FDA-approved, high affinity (at least one of the activity constants K_i, K_d, IC50 or EC50 is below 10 μM), and match the SARS-CoV-2 signature well (correlation > 0.86). The affinity column displays (and is colored by) \(-{\mathrm{log}\,}_{10}(\,\text{activity}\,)\). The correlation column displays (and is colored by) correlations between drug signatures and the reverse signature of SARS-CoV-2 infection based on the overparameterized autoencoder embedding. Discovered drug targets generally fall into two categories: serine/threonine protein kinases (light yellow) and receptor tyrosine kinases (dark yellow). The remaining drug targets are in white. The protein name corresponding to each gene is included.