We have interrogated the database Drugs.com for detecting any drug-drug interactions that had been reported among any pair of these 27 drugs. In total we have found 7 “major”, i.e., highly clinically significant, drug-drug interactions indicating that such combinations should be avoided because the risk of the interaction outweighs the benefit. Additionally we identified one “moderately” clinically significant drug-drug interaction, such that this combination should usually be avoided or use it only under special circumstances. The pairs of drugs displaying interactions are illustrated in the form of a graph in Fig. 6, where major interactions are marked in dark red and the moderate one in dark blue. Three other drugs: chlomezanone, panobinostat, and fedratinib are known to have interactions with foods according to the information in the same database.

Some of these 27 drugs: apabetalone (atherosclerosis and associated cardiovascular disease), romidepsin (anticancer agent), silmitasertib (inhibitor of protein kinase CK2), ozanezumab (a monoclonal antibody designed for the treatment of ALS and multiple sclerosis), procaine (local anesthetic), azacitidine (chemotherapy drug), amlexanox (anti-inflammatory antiallergic immunomodulator) and volociximab (antitumoral chimeric monoclonal antibody), form a cluster of drugs free of undesirable drug-drug interactions. The list may also include ellagic acid, which is a natural product found in several fruits and vegetables. The reason is that none of the previously mentioned drugs is known to have interactions with food. The importance of this list is that some of these drugs inhibit proteins that are involved in several of the organs/systems affected by COVID-19, while others are more specific for a smaller number of them. For instance, ellagic acid, apabalone and romidepsin interact with proteins involved in 7 of the 12 organs/systems damaged by COVID-19, while volociximab interacts with proteins involved in one of these organs/systems. In Fig. 7 (Table S3) we illustrate the connection between these organs/diseases through a few representative drugs found in this work. In this multigraph, every node correspond to one of the organs/systems affected by COVID-19 and they are connected by a colored edge if one of the nine drugs found here inhibits proteins involved in both diseases. From the point of view of the organs/systems damaged by COVID-19, the cardiovascular and immunological systems are the ones having more drugs targeting proteins which are affected by SARS-CoV-2, followed by the lymphatic and musculoskeletal ones. On the other side of the coin, the gastrointestinal, hepatic and metabolic systems have only one repurposable drug candidate each. The graph in Fig. 7 allows the selection of drug combinations for treating different sets of organs/systems damaged by COVID-19. For treating all of them it is necessary to find combination of drugs (edges of the graph) that cover all the diseases (nodes), which is achieved by mean of spanning trees. One example is given by the combination of romidepsin, silmitasertib, apabetalone and azacitidine, which is illustrated in the same Figure.