Fig 1.
Overview of the in silico approach showing the main phases employed to simulate the MoA of dexamethasone and tocilizumab with respect to COVID-19 evoked ARDS, including: 1) data compilation for molecular characterization of COVID-19 evoked ARDS, dexamethasone and tocilizumab obtained from literature review; 2) mathematical model generation using the validated top-down systems biology- and AI-based TPMS approach; and 3) data analyses employing model outputs. AI, artificial intelligence; ARDS, Acute respiratory distress syndrome; MoA, mechanism of action; TPMS, Therapeutic Performing Mapping Systems.
Table 1.
Summary of the drug characterization at target level.
Fig 2.
COVID-19 evoked ARDS interactome.
Human protein networks around COVID-19 evoked ARDS molecular pathophysiology considering all disease effectors and their direct interactors. General overview (A) and centred on the relationship of COVID-19 evoked ARDS effectors to tocilizumab (B) and dexamethasone (C) drug targets. Image created with Cytoscape 3.7.0 [56]. DEXA, dexamethasone; ICS, Inflammatory cytokine storm; LED, Lung epithelial damage; PF, Pulmonary fibrosis; PSB, Pneumonia and shortness of breath; TCZ, tocilizumab.
Fig 3.
Mechanism of action of dexamethasone.
Figure created to represent TPMS MoA predictions using Graphviz software. All links have been manually reviewed: the number of the links correspond to the reference code (link number) in S5 Table. Green arrows show activation; red line shows inhibition; blue lines show complex or dual relationships; broken-lined circles indicate a node that contains more than one protein, all acting in the MoA in the same way.
Fig 4.
Mechanism of action of tocilizumab.
Figure created to represent TPMS MoA predictions using Graphviz software. All links have been manually reviewed: the number of the links correspond to the reference code (link number) in S6 Table. Green arrows show activation; red line shows inhibition; broken-lined circles indicate a node that contains more than one protein, all acting in the MoA in the same way.
Fig 5.
Mechanism of action of dexamethasone and tocilizumab as combined therapy.
Consequences of the molecular modulation based on known proteins function and role in COVID-19 evoked ARDS is indicated for biological interpretation. A) shows the intracellular mechanisms of each drug, as predicted by the models; B) shows the known pathological situation in the alveolus in COVID-19 evoked ARDS, immune components implicated and pathological processes, as well as the drugs can action; C) summarises dexamethasone and tocilizumab effects on specific proteins and pathological processes in COVID-19 evoked ARDS; and classified in each of the studied motives (blue: mainly modulated by dexamethasone, orange: mainly modulated by tocilizumab, black: modulated by both drugs).
Fig 6.
Impact of dexamethasone and tocilizumab over COVID-19 evoked ARDS pathophysiological motives.
(A) Percentage of altered effectors reversed by each drug in each specific COVID-19 evoked ARDS motive. (B) Intensity of response (W-Signal) to each drug and the combination in the COVID-19 evoked ARDS specific motive, according to the simulated models.
Fig 7.
Effector protein heatmap activated for each model (dexamethasone and tocilizumab).
Heatmap of the average predicted protein activity induced by dexamethasone and tocilizumab over the effectors of the pathology. The vertical bars indicate the pathological effect of the effectors (ARDS sign: 1 if activated in the pathology, -1 if inhibited in the pathology); which COVID-19 evoked ARDS motives the proteins are assigned (Effector in motive) and whether the models reflect an effect of each drug over each effector (Modulated by drugs, considering |0.3| as the threshold of modulation and of modulation difference between drugs).
Fig 8.
Summary and overview of the biological processes modulated by the combination of dexamethasone and tocilizumab, according to our mathematical models. Proteins activated and inhibited by the pharmacological action of each drug were subjected to hypergeometric enrichment analysis independently, providing upregulated and downregulated processes respectively (modulated processes appear in both upregulated and downregulated analyses). This summary shows the COVID-19 evoked ARDS related processes modulated by the drugs. As indicated in the legend, colours indicate if the effect was shared between drugs (black) or are exclusive of dexamethasone (blue) or tocilizumab (orange).