Drug combinations, offering increased therapeutic efficacy and reduced toxicity, play an important role in treating various viral infections65. However, our ability to identify and validate effective combinations is limited by a combinatorial explosion, driven by both the large number of drug pairs and dosage combinations. In our recent study, we proposed a novel network-based methodology to identify clinically efficacious drug combinations28. Relying on approved drug combinations for hypertension and cancer, we found that a drug combination was therapeutically effective only if it was captured by the “Complementary Exposure” pattern: the targets of the drugs both hit the disease module, but target separate neighborhoods (Fig. 6a). Here we sought to identify drug combinations that may provide a synergistic effect in potentially treating 2019-nCoV/SARS-CoV-2 with well-defined mechanism-of-action by network analysis. For the 16 potential repurposable drugs (Fig. 5a, Table 1), we showcased three network-predicted candidate drug combinations for 2019-nCoV/SARS-CoV-2. All predicted possible combinations can be found in Supplementary Table S6.
Fig. 6 Network-based rational design of drug combinations for 2019-nCoV/SARS-CoV-2.
a The possible exposure mode of the HCoV-associated protein module to the pairwise drug combinations. An effective drug combination will be captured by the “Complementary Exposure” pattern: the targets of the drugs both hit the HCoV–host subnetwork, but target separate neighborhoods in the human interactome network. ZCA and ZCB denote the network proximity (Z-score) between targets (Drugs A and B) and a specific HCoV. SAB denotes separation score (see Materials and methods) of targets between Drug A and Drug B. b–d Inferred mechanism-of-action networks for three selected pairwise drug combinations: b sirolimus (a potent immunosuppressant with both antifungal and antineoplastic properties) plus dactinomycin (an RNA synthesis inhibitor for treatment of various tumors), c toremifene (first-generation nonsteroidal-selective estrogen receptor modulator) plus emodin (an experimental drug for the treatment of polycystic kidney), and d melatonin (a biogenic amine for treating circadian rhythm sleep disorders) plus mercaptopurine (an antimetabolite antineoplastic agent with immunosuppressant properties).