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SynergyFinder: a web application for analyzing drug combination dose-response matrix data.

ABSTRACT: Rational design of drug combinations has become a promising strategy to tackle the drug sensitivity and resistance problem in cancer treatment. To systematically evaluate the pre-clinical significance of pairwise drug combinations, functional screening assays that probe combination effects in a dose-response matrix assay are commonly used. To facilitate the analysis of such drug combination experiments, we implemented a web application that uses key functions of R-package SynergyFinder, and provides not only the flexibility of using multiple synergy scoring models, but also a user-friendly interface for visualizing the drug combination landscapes in an interactive manner.The SynergyFinder web application is freely accessible at https://synergyfinder.fimm.fi ; The R-package and its source-code are freely available at http://bioconductor.org/packages/release/bioc/html/synergyfinder.html .jing.tang@helsinki.fi.

SUBMITTER: Ianevski A

PROVIDER: S-EPMC5554616 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:BackgroundQuantitative description of dose-response of a drug for complex systems is essential for treatment of diseases and drug discovery. Given the growth of large-scale biological data obtained by multi-level assays, computational modeling has become an important approach to understand the mechanism of drug action. However, due to complicated interactions between drugs and cellular targets, the prediction of drug efficacy is a challenge, especially for complex systems. And the biological systems can be regarded as networks, where nodes represent molecular entities (DNA, RNA, protein and small compound) and processes, edges represent the relationships between nodes. Thus we combine biological pathway-based network modeling and molecular docking to evaluate drug efficacy.ResultsNetwork efficiency (NE) and network flux (NF) are both global measures of the network connectivity. In this work, we used NE and NF to quantitatively evaluate the inhibitory effects of compounds against the lipopolysaccharide-induced production of prostaglandin E2. The edge values of the pathway network of this biological process were reset according to the Michaelis-Menten equation, which used the binding constant and drug concentration to determine the degree of inhibition of the target protein in the pathway. The combination of NE and NF was adopted to evaluate the inhibitory effects. The dose-response curve was sigmoid and the EC50 values of 5 compounds were in good agreement with experimental results (R(2) = 0.93). Moreover, we found that 2 drugs produced maximal synergism when they were combined according to the ratio between each EC50.ConclusionsThis quantitative model has the ability to predict the dose-response relationships of single drug and drug combination in the context of the pathway network of biological process. These findings are valuable for the evaluation of drug efficacy and thus provide an effective approach for pathway network-based drug discovery.

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SynergyFinder: a web application for analyzing drug combination dose-response matrix data.

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