Discovering Anti-platelet Drug Combinations with an Integrated Model of Activator-Inhibitor Relationships, Activator-Activator Synergies and Inhibitor-Inhibitor Synergies
Fig 3
Identification of activator-activator synergy, inhibitor-inhibitor synergy, and activator-inhibitor combination effects.
Combination experiments of activators and inhibitors. (A) Mean log10 ADP release across platelets from 10 blood donors are shown, with green indicating platelet activation. Combinations of activator and inhibitors. Single and double doses (concentrations) of each activator alone are shown at the bottom; single and double doses of each inhibitor in the presence of a cocktail of all five activators are shown to the right; resting and cocktail are shown bottom right (B) Activator-activator combinations and inhibitor-inhibitor combinations, log(AAU) ADP release. Inhibitor-inhibitor data represents the inhibition of a cocktail of all five agonists. (C) To more easily visualize the data allowing for the differences in levels of activation among the five activators, a simple correction of the data is shown, with the values in panel A subtracted by the value of the single dose activator alone (thus, for CaXi the value is 4.90–4.97 = −0.07). Four significant activator-inhibitor combinations identified by statistical modeling (see text) are highlighted within a white box. Two of these lie on the diagonal, as expected a priori. (D) As for panel B, but calculated to display the difference of the activation or inhibition from the most effective double dose of either the first or the second agent within the combination (thus, for PiTi the value is 5.29–5.13 = 0.16). Positive synergy corresponds to more combined stimulation for the activator-activator pairs, indicated in magenta, and also to less combined stimulation for the inhibitor-inhibitor pairs, which are also indicated in magenta (i.e. magenta implies strong positive synergy of either activation, or of inhibition).