Discovering Anti-platelet Drug Combinations with an Integrated Model of Activator-Inhibitor Relationships, Activator-Activator Synergies and Inhibitor-Inhibitor Synergies
Fig 7
Integrated modelling and validation of synergy and activator-inhibitor combination effects.
(A) a schematic of the integrated model (S4 Table), investigating the influence of five activators (green dots) and five inhibitors (red dots) on platelet activation. Each solid line (10 black main effects, 4 purple activator-inhibitor combination effects, 3 red inhibitor-inhibitor synergy effects, 2 green activator-activator synergy effects) represents a parameter within the multiple regression model predicting platelet activation. The five receptors and the kinase shown in the model are not explicitly modelled since there is no direct data on their activation states. The predictions of this model were used to assess the impact of all possible three way combinations of inhibitors on platelets activated by a cocktail of five activators (S5 Table). (B) testing the most strongly predicted inhibitor triple combination. This shows that the most strongly predicted three-way combination of Xi, Ai, Ti had a clearly stronger effect than the alternative Xi, Ai, Pi combination which was ranked more weakly by the predictive model (p = 0.0003).