Chemical composition and pharmacological mechanism of Ephedra-Glycyrrhiza drug pair  against coronavirus disease 2019 (COVID-19)

Abstract

Background: Coronavirus disease 2019 (COVID-19) is currently spreading all over the world, and the prospect of a very rapid increase in COVID-19 cases prompted us to seek effective antiviral therapeutics, from the identification of possible drugs to their potential mechanisms. Purpose: The aim of this study was to explore the efficacy of the Ephedra-Glycyrrhiza (EG) drug pair on coronavirus disease 2019 (COVID-19) by network pharmacology and molecular docking. Methods: The main active compounds, target information, meridians and properties of EG were obtained through the TCMSP and ETCM databases. The targeted information of COVID-19 was acquired from the GeneCards database. EG drug pair applied diseases were analysed by DAVID and the drug-bank database, and visualized by Rstudio and Cytoscape 3.7.2. Then, we carried out targeted intersection of the EG drug pair and COVID-19 to map the compound-target-disease interactions and visualize them with Cytoscape 3.7.2 and Venny 2.1. In addition, the enrichment analysis of the GO and KEGG pathways were visualized with Rstudio and PathVisio software through the DAVID database. Finally, we carried out the molecular docking of the EG active compounds with M hydrolase (Mpro), spike protein (S protein) and angiotensin-converting enzyme 2 (ACE2), and the binding modes between GE and the protein were verified via molecular dynamics (MD) simulation. Results: We identified 112 active EG compounds by network pharmacological analysis. Drug pair enrichment analysis demonstrated that these compounds may participate in the cAMP, PI3K-Akt, JAK-STAT and chemokine signalling pathways, which had a high correlation with respiratory system, nervous system, blood circulation system and digestive system related diseases. Pathway analysis between EG and COVID-19 showed that the key targets were TNF, IL2, FOS, ALB and PTGS2. They may regulate the PI3K-Akt signalling pathway and natural killer cell-mediated cytotoxicity to play roles in immune regulation, organ protection, antiviral, immune regulation, and organ protection as well as having antiviral effects. Molecular docking results showed that the active EG compounds bind well to Mpro, S protein and ACE2. The binding modes between the active compounds of the EG and protein were verified via MD simulation. Conclusion: The EG drug pair can treat COVID-19 through multiple targets and pathways, which can provide a theoretical basis for further study of the mechanism of action of the EG drug pair on COVID-19.