COVID-19 Research Paper Volume 13, Issue 21 pp 23913—23935

New tale on LianHuaQingWen: IL6R/IL6/IL6ST complex is a potential target for COVID-19 treatment

Zhao Tianyu1, , Cui Xiaoli1, , Wang Yaru1, , Zhang Min1, , Yue Fengli1, , He Kan1, , Chen Li1, , Li Jing1, ,

  • 1 Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province 130021, People’s Republic of China

Received: April 28, 2021       Accepted: October 25, 2021       Published: November 3, 2021
How to Cite

Copyright: © 2021 Tianyu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


LianHuaQingWen (LHQW) improves clinical symptoms and alleviates the severity of COVID-19, but the mechanism is unclear. This study aimed to investigate the potential molecular targets and mechanisms of LHQW in treating COVID-19 using a network pharmacology-based approach and molecular docking analysis. The main active ingredients, therapeutic targets of LHQW, and the pathogenic targets of COVID-19 were screened using the TCMSP, UniProt, STRING, and GeneCards databases. According to the “Drug-Ingredients-Targets-Disease” network, Interleukin 6 (IL6) was identified as the core target, and quercetin, luteolin, and wogonin as the active ingredients of LHQW associated with IL6. The response to lipopolysaccharide was the most significant biological process identified by gene ontology enrichment analysis, and AGE-RAGE signaling pathway activation was prominent based on the interaction between LHQW and COVID-19. Protein-protein docking analysis showed that IL6 receptor (IL6R)/IL6/IL6 receptor subunit beta (IL6ST) and Spike protein were mainly bound via conventional hydrogen bonds. Furthermore, protein-small molecule docking showed that all three active ingredients could bind stably in the binding model of IL6R/IL6 and IL6ST. Our findings suggest that LHQW may inhibit the lipopolysaccharide-mediated inflammatory response and regulate the AGE-RAGE signaling pathway through IL6. In addition, the N-terminal domain of the S protein of COVID-19 has a good binding activity to IL6ST, and quercetin and wogonin in LHQW may affect IL6ST-mediated IL6 signal transduction and a large number of signaling pathways downstream to other cytokines by directly affecting protein-protein interaction. These findings suggest the potential molecular mechanism by which LHQW inhibits COVID-19 through the regulation of IL6R/IL6/IL6ST.


3D: 3-dimension; ACE2: angiotensin I converting enzyme 2; AGE: Advanced Glycation End Product; AKT1: AKT serine/threonine kinase 1; ALB: Albumin; ARDS: Acute Respiratory Distress Syndrome; Arg: arginine; Asn: asparagine; Asp: aspartic acid; BAX: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; BP: Biological Process; CASP3: Caspase 3; CC: Cellular Component; CCL2: C-C motif chemokine ligand 2; CHARMm: Chemistry at HARvard Macromolecular Mechanics; CNTF: ciliary neurotrophic factor; COVID-19: Corona Virus Disease 2019; CS: Cytokine Storm; CSF: Colony Stimulating Factor; CXCL10: C-X-C motif chemokine ligand 10; CXCL8: C-X-C motif chemokine ligand 8; Cys: cysteine; DL: Drug-Likeness; FOS: Fos proto-oncogene, AP-1 transcription factor subunit; Gln: glutamine; GO: Gene Ontology; His: histidine; ICAM1: Intercellular Adhesion Molecule 1; IFN: Interferon; IFNG: Interferon Gamma; IL10: Interleukin 10; IL1A: Interleukin 1 alpha; IL1B: Interleukin 1 beta; IL2: Interleukin 2; IL4: Interleukin 4; IL6: Interleukin 6; IL6R: Interleukin 6 receptor; IL6ST: Interleukin 6 receptor subunit beta; IL7: Interleukin 7; IL8: Interleukin 8; KEGG: Kyoto Encyclopedia of Genes and Genomes; LHQW: LianHuaQingWen; LIF: leukemia inhibitory factor; LPS: Lipopolysaccharide; Lys: lysine; mAb: monoclonal antibody; MAPK1: Mitogen-activated protein kinase 1; MAPK14: Mitogen-activated protein kinase 14; MAPK3: Mitogen-activated protein kinase 3; MAPK8: Mitogen-activated protein kinase 8; MCP-1: Monocyte Chemoattractant Protein-1; MERS-CoV: Middle East respiratory syndrome coronavirus; MF: Molecular Function; MODS: Multiple Organ Dysfunction Syndrome; NF-κB: nuclear transcription factor-κB; NMPA: National Medical Products Administration; NOS3: Nitric Oxide Synthase 3; NTD: N-terminus domain; OB: Oral Bioavailability; OSM: oncostatin-M; PDB: Protein Data Bank; PPI: protein-protein interaction; PRKCA: Protein kinase C alpha; PTGS2: Prostaglandin-endoperoxide synthase 2; RAGE: receptor for Advanced Glycation End Product; RBD: receptor-binding domain; RCSB: Research Collaboratory for Structural Bioinformatics; RELA: RELA proto-oncogene, NF-kB subunit; RMSD: root-mean-square deviation; S: Spike; SARS-CoV: SARS coronavirus; Ser: serine; SERPINE1: Serpin Family E Member 1; STAT1: Signal Transducer and Activator of Transcription 1; TCM: traditional Chinese medicine; TCMSP: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform; Thr: threonine; TNF: Tumor Necrosis Factors; TP53: Tumor Protein p53; Trp: tryptophan; Tyr: tyrosine; UniProt: Universal Protein Resource.