Fig 1.
A schematic overview of SynToxProfiler.
The dose-response data from drug combination screening, measured in both diseased (e.g. patient-derived cells) and healthy control cells (e.g. PBMCs), is provided as input to SynToxProfiler (left panel). Then, SynToxProfiler quantifies drug combination efficacy and synergy (using combination responses in diseased cells) as well as toxicity (using combination responses in control cells) for each drug pair (middle panel), and summarizes them into integrated synergy, toxicity and efficacy (STE) score. The increase in red color gradient in the efficacy and toxicity matrix (middle panel) denotes an increase in percentage inhibition of cancer and healthy cells, respectively. The color gradient from white to red in the synergy matrix shows the shift of drug interactions from antagonism to synergy. The STE score is further used to rank and visualize the drug pairs in 2D or 3D interactive plots (right panel). The color gradient from blue to red in the right panel depicts an increasing STE score from low to high.
Table 1.
Ranking of 20 in-house measured combinations based on STE scores calculated from the most synergistic area of dose-response matrix in T-PLL and healthy control cells.
Fig 2.
STE score considers both synergy and selective efficacy when prioritizing potent drug combinations.
(A) 3D surface shows increase in STE score with increasing synergy and selective efficacy scores across 77 antiviral combinations measured in Huh7 liver cell line infected with Ebola virus (the arrow marks the gradient of the increase in STE score). The 3D surface is fitted by a generalized additive model with a tensor product smooth, implemented in mgcv R package. The color gradient from blue to red represents the low to high STE score for drug combinations. (B) Scatter plot showing the overlap in the top hits selected on the basis of STE and Synergy (red), STE and selective efficacy(orange), and selective efficacy and synergy(blue) scores. The dotted vertical line denotes the overlap between the top 10% combinations selected based on any of the three scores.
Fig 3.
SynToxProfiler penalizes for toxicity of drug pairs while ranking top hits.
The efficacy, toxicity, and synergy matrices for the top drug pairs selected based on the highest STE score (clomiphene citrate and sertraline HCL, upper panel) and the highest synergy score (toremifene citrate and apilimod, lower panel). The synergy was calculated using the ZIP model implemented in SynergyFinder [21]. The square with dotted line denotes the 3x3 concentration range with the most synergistic area in the dose-response matrix.