Related Experiment Video
Updated: Apr 11, 2026
High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method
Published on: May 21, 2018
A Network-Based Target Overlap Score for Characterizing Drug Combinations: High Correlation with Cancer Clinical
Balázs Ligeti1, Zsófia Pénzváltó2, Roberto Vera3
1Faculty of Information Technology, Pázmány Péter Catholic University, Budapest, Hungary.
Abstract:
Drug combinations are highly efficient in systemic treatment of complex multigene diseases such as cancer, diabetes, arthritis and hypertension. Most currently used combinations were found in empirical ways, which limits the speed of discovery for new and more effective combinations. Therefore, there is a substantial need for efficient and fast computational methods. Here, we present a principle that is based on the assumption that perturbations generated by multiple pharmaceutical agents propagate through an interaction network and can cause unexpected amplification at targets not immediately affected by the original drugs. In order to capture this phenomenon, we introduce a novel Target Overlap Score (TOS) that is defined for two pharmaceutical agents as the number of jointly perturbed targets divided by the number of all targets potentially affected by the two agents. We show that this measure is correlated with the known effects of beneficial and deleterious drug combinations taken from the DCDB, TTD and Drugs.com databases. We demonstrate the utility of TOS by correlating the score to the outcome of recent clinical trials evaluating trastuzumab, an effective anticancer agent utilized in combination with anthracycline- and taxane- based systemic chemotherapy in HER2-receptor (erb-b2 receptor tyrosine kinase 2) positive breast cancer.
Insights
Computational methods can accelerate the discovery of effective drug combinations for complex diseases. A new Target Overlap Score (TOS) predicts combination efficacy by analyzing drug-target interactions in biological networks.
Area of Science:
- Computational biology
- Pharmacology
- Systems biology
Background:
- Drug combinations are crucial for treating complex diseases like cancer, but discovery is often empirical.
- Existing methods for identifying effective drug combinations are slow, necessitating faster computational approaches.
Purpose of the Study:
- To introduce a novel computational method for predicting the efficacy of drug combinations.
- To develop a new metric, the Target Overlap Score (TOS), for quantifying drug combination effects.
Main Methods:
- Developed the Target Overlap Score (TOS) based on the principle of drug-induced perturbations propagating through biological interaction networks.
- Defined TOS as the ratio of jointly perturbed targets to all potentially affected targets by two agents.
- Validated TOS using established drug combination databases (DCDB, TTD, Drugs.com) and clinical trial data for trastuzumab in breast cancer.
Main Results:
- The novel Target Overlap Score (TOS) demonstrated a correlation with known beneficial and deleterious drug combinations.
- TOS showed utility in predicting clinical outcomes for combination therapies, specifically in HER2-positive breast cancer treatment.
Conclusions:
- The Target Overlap Score (TOS) offers an efficient computational approach to predict drug combination efficacy.
- This method can accelerate the discovery of novel and effective combination therapies for complex diseases, improving treatment strategies.
Related Concept Videos
01:14Agonism and Antagonism: Quantification
To quantify these effects, researchers use a dose-response curve, which provides valuable information about the potency and efficacy of a drug. Potency refers to...
01:27Combined Effects of Drugs: Synergism
Such synergistic combinations...
01:26Drug Discovery: Overview
01:29Pharmacogenomics: Identification of New Drug Targets
01:30Combined Effects of Drugs: Antagonism
The most common type is receptor antagonism, where one drug acts as an antagonist to block the effects of another drug by...
01:26Targets for Drug Action: Overview
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...