Exploration of molecular targets and mechanisms of Chinese medicinal formula Acacia Catechu ‐Scutellariae Radix in the treatment of COVID‐19 by a systems pharmacology strategy

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In China, the Acacia catechu (AC)-Scutellariae Radix (SR) formula has been widely used for pulmonary infection in clinical practice for several centuries. However, the potential role and mechanisms of this formula against COVID-19 remains unclear. The present study was designed to dissect the active ingredients, molecular targets, and the therapeutic mechanisms of AC-SR formula in the treatment of COVID-19 based on a systems pharmacology strategy integrated by ADME screening, target prediction, network analysis, GO and KEGG enrichment analysis, molecular docking, and molecular dynamic (MD) simulations. Finally, Quercetin, Fisetin(1-), kaempferol, Wogonin, Beta-sitosterol, Baicalein, Skullcapflavone II, Stigmasterol were primarily screened to be the potentially effective active ingredients against COVID-19. The hub-proteins were TP53, JUN, ESR1, MAPK1, Akt1, HSP90AA1, TNF, IL-6, SRC, and RELA. The potential mechanisms of AC-SR formula in the treatment of COVID-19 were the TNF signaling pathway, PI3K-Akt signaling pathway and IL-17 signaling pathway, etc. Furthermore, virtual docking revealed that baicalein, (+)-catechin and fisetin(1-) exhibited high affinity to SARS-CoV-2 3CLpro, which has validated by the FRET-based enzymatic inhibitory assays with the IC50 of 11.3, 23.8, and 44.1 μM, respectively. And also, a concentration-dependent inhibition of baicalein, quercetin and (+)-catechin against SARS-CoV-2 ACE2 was observed with the IC50 of 138.2, 141.3, and 348.4 μM, respectively. These findings suggested AC-SR formula exerted therapeutic effects involving "multi-compounds and multi-targets." It might be working through directly inhibiting the virus, improving immune function, and reducing the inflammatory in response to anti-COVID-19. Ultimately, this study would provide new perspective for discovering potential drugs and mechanisms against COVID-19.