Exploring the active compounds of traditional Mongolian medicine in intervention of novel coronavirus (COVID-19) based on molecular docking method

Abstract

Objective: This article intends to use molecular docking technology to find potential inhibitors that can respond to COVID-19 from active compounds in Mongolian medicine.

Methods: Mongolian medicine with anti-inflammatory and antiviral effects is selected from Mongolian medicine prescription preparations. TCMSP, ETCM database and document mining methods were used to collect active compounds. Swiss TargetPrediction and SuperPred server were used to find targets of compounds with smiles number. Drugbank and Genecard database were used to collect antiviral drug targets. Then the above targets were compared and analyzed to screen out antiviral targets of Mongolia medicine. Metascape database platform was used to enrich and analyze the GO (Gene ontology) annotation and KEGG pathway of the targets. In view of the high homology of gene sequences between SARS-CoV-2 S-protein RBD domain and SARS virus, as well as their similarities in pathogenesis and clinical manifestations, we established SARS-CoV-2 S-protein model using Swiss-Model. The ZDOCK protein docking software was applied to dock the S-protein with the human angiotensin ACE2 protein to find out the key amino acids of the binding site. Taking ACE2 as the receptor, the molecular docking between the active ingredients and the target protein was studied by AutoDock molecular docking software. The interaction between ligand and receptor is applied to provide a choice for screening anti-COVID-19 drugs.

Results: A total of 253 active components were predicted. Metascape analysis showed that key candidate targets were significantly enriched in multiple pathways related to different toxins. These key candidate targets were mainly derived from phillyrin and chlorogenic acid. Through the protein docking between S-protein and ACE2, it is found that Glu329/Gln325 and Gln42/Asp38 in ACE2 play an important role in the binding process of the two. The results of molecular docking virtual calculation showed that phillyrin and chlorogenic acid could stably combine with Gln325 and Gln42/Asp38 in ACE2, respectively, which hindered the combination between S- protein and ACE2.

Conclusion: Phillyrin and chlorogenic acid can effectively prevent the combination of SARS-CoV-2 S-protein and ACE2 at the molecular level. Phillyrin and chlorogenic acid can be used as potential inhibitors of COVID-19 for further research and development.

Keywords: ACE2; COVID-19; Chlorogenic acid; Mongolian medicine; Phillyrin; S-protein; SARS-CoV-2.

Graphical abstract

Fig. 1

The flow diagram for screening and verifying Mongolian medicine compounds.

Fig. 2

A:Venn diagram for comparative analysis of compound targets and antiviral drug targets; B: The Metascape platform to select the top GO annotation results and KEGG pathway; C: The map of differential gene enrichment interaction, including 20 groups of enrichment results; D: The network map constructed according to the enrichment degree, the darker the color is, the more genes are enriched into the pathway.

Fig. 3

A:The 3D structure of phillyrin and chlorogenic acid. B: A fully connected interaction network of related proteins of all genes. C: module substructure identified in the interaction network.

Fig. 4

The SARS-CoV-2 S-protein model constructed.

Fig. 5

A: Amino acid sequence alignment of RBD domain of coronavirus S-protein. Residues 442, 472, 479, 487, 491 (numbered according to SARS-CoV S-protein sequence) are important residues interacting with human ACE2 molecules. B: The combination of SARS-CoV-2 S-protein and ACE2 protein. C:The combination of SARS-CoV-2 S-protein and ACE2 protein in pyMOL software view.

Fig. 6

Structural simulation of SARS-CoV-2 S-protein docking with human ACE2 molecule. Left panel: This area shows the hydrogen bond interaction between Tyr436 in S- protein and Asp38/Gln42 in ACE2. The relevant residues are presented in ball and stick representations. Right panel: This region shows the hydrogen bond interaction between Arg426 in S protein and Gln325/Glu329 in ACE2.

Fig. 7

A:the molecular docking between phillyrin and ACE2. Phillyrin and Gln325 in ACE2 are bonded to each other through hydrogen bonds; B: The binding situation of chlorophenolic acid and ACE2, and the chlorophenolic acid interacts with Asp38/Gln42 in ACE2 through hydrogen bonds.