Network pharmacology and computer-aided drug design to explored potential targets of Lianhua Qingwen and Qingfei Paidu decoction for COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, has spread globally, affecting people's lives worldwide and hindering global development. Traditional Chinese Medicine (TCM) plays a unique role in preventing and treating COVID-19. Representative prescriptions for the COVID-19 treatment, Lianhua Qingwen (LHQW) and Qingfei Paidu Decoction (QFPD), effectively alleviate COVID-19 symptoms, delaying its progression and preventing its occurrence. Despite the extensive similarity in their therapeutic effects, the mechanisms and advantages of LHQW and QFPD in in treating mild-to-moderate COVID-19 remain elusive. To characterize the mechanisms of LHQW and QFPD in treating COVID-19, we used integrated network pharmacology and system biology to compare the LHQW and QFPD components, active compounds and their targets in Homo sapiens. LHQW and QFPD comprise 196 and 310 active compounds, some of which have identical targets. These targets are enriched in pathways associated with inflammation, immunity, apoptosis, oxidative stress, etc. However, the two TCM formulas also have specific active compounds and targets. In LHQW, arctiin, corymbosin, and aloe-emodin target neurological disease-related genes (GRM1 and GRM5), whereas in QFPD, isofucosterol, baicalein, nobiletin, oroxylin A, epiberberine, and piperlonguminine target immunity- and inflammation-related genes (mTOR and PLA2G4A). Our findings indicate that LHQW may be suitable for treating mild-to-moderate COVID-19 with nervous system symptoms. Moreover, QFPD may effectively regulate oxidative stress damage and inflammatory symptoms induced by SARS-CoV-2. These findings may provide references for the clinical application of LHQW and QFPD.

Keywords: COVID-19; GRM1/5; arctiin; systems biology; traditional Chinese medicine; β-carotene.

FIGURE 1

Main channel tropism of Lianhua Qingwen (LHQW) and Qingfei Paidu Decoction (QFPD) based on the TCM theory.

FIGURE 2

Protein interaction network (PIN) construction and network topology analysis. (A) PIN was constructed using the common host targets of LHQW and QFPD. (B) PIN topology analysis was performed using the Network Analyzer of the Cytoscape software. (C–E) The significant module was identified from the PIN using the molecular complex detection (MCODE) method with a score >4.0; the red and yellow nodes represent hub genes, yellow represents the lower degree and red represents the higher degree.

FIGURE 3

Gene Ontology (GO) and KEGG enrichment analysis of common genes of LHQW and QFPD targeted during the treatment of mild-to-moderate COVID-19. (A) GO analysis was performed for the top 10 GO terms identified; X-axis represents GO term categories, while the y-axis represents the enrichment score. (B) A KEGG analysis of the genes was performed, and the top 15 pathways are shown. The color of the dot represents the p-value. The dot size represents the number of target genes enriched in the pathway.

FIGURE 4

“TCM component–active compound–specific target” networks and protein modules of LHQW and QFPD. The green diamond represents the TCM components, the orange triangle represents the active compounds, and the cyan fusiform represents the network targets. (A) Interconnection between TCM components, active compounds, and the specific targets of the active compounds in LHQW. (B) Interconnection between TCM components, active compounds, and their specific targets of the active compounds in QFPD. (C) The significant module identified from the specific targets of LHQW. (D) The significant module identified from the specific targets of QFPD.

FIGURE 5

Molecular models of active compounds with specific key LHQW target genes. (A) Molecular model of arctiin, (B) β-carotene, (C) and aloe-emodin binding to GRM1. (G) Molecular model of arctiin, (H) corymbosin, (I) and aloe-emodin binding to GRM5. Yellow dashed lines represent H-bonds, thick pink sticks represent the active compounds, and thick green sticks represent residues in the protein-binding site. (D) Interactions between arctiin, (E) β-carotene, (F) aloe-emodin, and GRM1. (J) Interaction between arctiin, (K) corymbosin, (L) aloe-emodin, and GRM5. Blue dashed lines represent H-bonds between the active compounds and residue backbones, and green dashed lines represent H-bonds between the active compounds and residue sidechains. The dashed lines point to the acceptor.

FIGURE 6

Molecular models of active compounds with specific QFPD target genes. (A) Molecular model of isofucosterol binding to mTOR. (B) Molecular model of baicalein, (C) nobiletin, (D) oroxylin A, (I) epiberberine, (G) piperlonguminine, (K) baicalein, (L) and isofucosterol binding to PLA2G4A. Yellow dashed lines represent H-bonds, thick pink sticks represent active compounds, and thick green sticks represent residues at the protein-binding site. (E) Interaction of isofucosterol, (F) baicalein, (G) nobiletin, and mTOR. (H) Interaction of oroxylin A, (M) epiberberine, (N) piperlonguminine, (O) baicalein, (P) isofucosterol, and PLA2G4A. Blue dashed lines represent H-bonds between the active compounds and residue backbones, and the green dashed lines indicate H-bonds between the active compounds and residue sidechains. The dashed lines point to the acceptor.

FIGURE 7

Root mean square deviation (RMSD) of molecular dynamic simulations. (A) RMSD of arctiin binding to GRM1. (B) RMSD of β-carotene binding to GRM1 (C) RMSD of arctiin binding to GRM5.