OBJECTIVE To explore the potential mechanisms and bioactive compounds of licorice against COVID-19 based on a multidimensional interaction of "component-disease-symptom-target".

METHODS Firstly, candidate target sets for licorice components were obtained from the ETCM2.0 database based on the Encyclopedia of Traditional Chinese Medicine, and the disease symptoms and associated target sets for COVID-19 were derived from the GeneCards and HPO databases. And then a protein interaction network was constructed using the String database (version 12.0). By calculating topological eigenvalues and functional enrichment analysis, the potential mechanisms of action were explored. Combined with Schrödinger molecular docking virtual screening, candidate pharmacodynamic substances were identified. Fluorescence resonance energy transfer was used for experimental verification.

RESULTS Licorice might improve symptoms of COVID-19 (fever, chest pain and so on) by regulating the imbalance of "immune-inflammation" network and signal transduction abnormalities during the development and progress of COVID-19, such as coronavirus disease-COVID-19, Toll-like receptor signaling pathway and NOD-like receptor signaling pathway. The components, such as Isoschaftoside and Hesperidin, were identified to possess high binding affinity with the critical enzymes for viral replication. Isoschaftoside, Hesperidin, Isoliquiritin apioside and Vicenin-2 exhibited varying degrees of inhibition on the enzyme of 3CLpro at different concentrations while excluding the interference of the compounds' fluorescence.

CONCLUSION Through experimental verification using a multidimensional interaction network of "component-disease-symptom-target", the key pharmacologically active substances of licorice in the fight against COVID-19 are preliminarily identified, and their mechanism of action through overall regulation is elucidated.