Discovery of the Major Bioactive Compounds and Action Mechanisms Responsible for the Protective Effects of Xiaochaihu Decoction on COVID-19 Based on Molecular Docking and Network Pharmacology Methods

OBJECTIVE To explore the active constituents and mechanism of action in Xiaochaihu decoction(XCHD) for treatment of COVID-19, and provide a reference for its clinical application. METHODS The chemical constituents in XCHD were collected by using Traditional Chinese Medicine Systems Pharmacology Database(TCMSP). Further molecular docking study was performed to evaluate the interactions between these constituents and the ACE2, MPro, and PLP target proteins. The targets of constituents were collected by using TCMSP and Comparative Toxicogenomics Database(CTD). Protein-protein interaction(PPI) data was constructed by using String website to screen key targets. The "herb-active constituent-key target" network was constructed by using Cytoscape software, followed by topology analysis. Moreover, KEGG pathway analysis was performed on screened key targets with the DAVID database to predict the protective mechanism of XCHD on COVID-19. RESULTS Molecular docking results showed that the number of active ingredients in XCHD binding with ACE2, MPro, and PLP with Libdockscore>120 were 86, 114, and 105, respectively. For example, licorice glycoside E was nicely bound to ACE2, MPro and PLP. Saikosaponin C and ginsenoside Rh2 were nicely bound to ACE2. Troxerutin and protoporphyrin were nicely bound to Mpro. α-Spinasterol and supraene were nicely bound to PLP. Network topology analysis screened 118 core targets, the key targets involved PTGS2, AR, MAPK14, PPARG and GSK3B, etc. A total of 118 key targets were screened, such as PTGS2, AR, MAPK14, PPARG, and GSK3B. There were 124 key target-related active components, such as quercetin, wogonin, kaempferol, isorhamnetin, and (-)-catechin. Further KEGG pathway analysis revealed several key pathways which were probably involved in the treatment of COVID-19, including Influenza A pathway, Small cell lung cancer pathway, TNF signaling pathway, Toll-like receptor signaling pathway, PI3K-Akt signaling pathway, and HIF-1 signaling pathway. CONCLUSION The mechanisms of XCHD in the treatment of COVID-19 are summarized as following:① the active constituents can act on ACE2, MPro and PLP to inhibit the infection and reproduction of SARS-CoV-2. ② act on the targets such as PTGS2, TNF-α, and IL-6 to inhibit the cytokine release syndrome. ③ regulate the HIF-1 signaling pathway to alleviate hypoxemia.