Dissecting the molecular mechanism of cepharanthine against COVID-19, based on a network pharmacology strategy combined with RNA-sequencing analysis, molecular docking, and molecular dynamics simulation

https://doi.org/10.1016/j.compbiomed.2022.106298Get rights and content

Highlights

  • The first paper to systematically illustrate the core targets, crucial pathways and potential mechanism of cepharanthine in the treatment of COVID-19.

  • Using a novel strategy combining network pharmacology, RNA-sequencing analysis, molecular docking, and molecular dynamics simulation to determine the mechanism.

  • ACE2 and PI3K-Akt pathway play significant roles in cepharanthine against COVID-19.

Abstract

Objectives

Recently, it has been reported that cepharanthine (CEP) is highly likely to be an agent against Coronavirus disease 2019 (COVID-19). In the present study, a network pharmacology-based approach combined with RNA-sequencing (RNA-seq), molecular docking, and molecular dynamics (MD) simulation was performed to determine hub targets and potential pharmacological mechanism of CEP against COVID-19.

Methods

Targets of CEP were retrieved from public databases. COVID-19-related targets were acquired from databases and RNA-seq datasets GSE157103 and GSE155249. The potential targets of CEP and COVID-19 were then validated by GSE158050. Hub targets and signaling pathways were acquired through bioinformatics analysis, including protein-protein interaction (PPI) network analysis and enrichment analysis. Subsequently, molecular docking was carried out to predict the combination of CEP with hub targets. Lastly, MD simulation was conducted to further verify the findings.

Results

A total of 700 proteins were identified as CEP-COVID-19-related targets. After the validation by GSE158050, 97 validated targets were retained. Enrichment results indicated that CEP acts on COVID-19 through multiple pathways, multiple targets, and overall cooperation. Specifically, PI3K-Akt signaling pathway is the most important pathway. Based on PPI network analysis, 9 central hub genes were obtained (ACE2, STAT1, SRC, PIK3R1, HIF1A, ESR1, ERBB2, CDC42, and BCL2L1). Molecular docking suggested that the combination between CEP and 9 central hub genes is extremely strong. Noteworthy, ACE2, considered the most important gene in CEP against COVID-19, binds to CEP most stably, which was further validated by MD simulation.

Conclusion

Our study comprehensively illustrated the potential targets and underlying molecular mechanism of CEP against COVID-19, which further provided the theoretical basis for exploring the potential protective mechanism of CEP against COVID-19.

Keywords

Cepharanthine
COVID-19
ACE2
PI3K-Akt signal pathway
Network pharmacology
RNA-Sequencing
Molecular docking

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