Screening combinatorial perturbations via a bifurcation-based method

Compared with monotherapy, combination therapy is the first choice and the most promising method for the treatment of many complex diseases. Due to the wide variety of drugs, it is often difficult to choose desirable combination drugs with synergy and low risk. Additional research should always be done before combining drugs because the combinatorial effects can be synergistic, additive, or even antagonistic. Synergistic drugs work together to cause an effect greater than the sum of its parts. Some studies propose different approaches to detect synergism between two or more drugs. Based on the framework of bifurcation-based method, we propose an approach to screen another potential synergistic drug for a given drug. Different from other methods, the approach can help us screen and detect drugs which have a synergistic effect with a known drug, thus playing critical roles in combination therapy. In order to demonstrate the effectiveness of the approach, we apply it to three models, i.e. the zeroth-order reaction model, the galactose model, and the epithelial-to-mesenchymal transition network. The approach provides a theoretical basis for rational design of combination drugs and new use of old drugs.