In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 4 ( 2022-4-6), p. e0266632-
Abstract:
Interleukin 6 (IL-6) is a cytokine with various biological functions in immune regulation, hematopoiesis, and inflammation. Elevated IL-6 levels have been identified in several severe disorders such as sepsis, acute respiratory distress syndrome (ARDS), and most recently, COVID-19. The biological activity of IL-6 relies on interactions with its specific receptor, IL-6Rα, including the membrane-bound IL-6 receptor (mIL-6R) and the soluble IL-6 receptor (sIL-6R). Thus, inhibition of the interaction between these two proteins would be a potential treatment for IL-6 related diseases. To date, no orally available small-molecule drug has been approved. This study focuses on finding potential small molecules that can inhibit protein-protein interactions between IL-6 and its receptor IL-6Rα using its crystal structure (PDB ID: 5FUC). First, two pharmacophore models were constructed based on the interactions between key residues of IL-6 (Phe74, Phe78, Leu178, Arg179, Arg182) and IL-6Rα (Phe229, Tyr230, Glu277, Glu278, Phe279). A database of approximately 22 million compounds was screened using 3D-pharmacophore models, molecular docking models, and ADMET properties. By analyzing the interactive capability of successfully docked compounds with important amino acids, 12 potential ligands were selected for further analysis via molecular dynamics simulations. Based on the stability of the complexes, the high interactions rate of each ligand with the key residues of IL-6/IL-6Rα, and the low binding free energy calculation, two compounds ZINC83804241 and ZINC02997430, were identified as the most potential IL-6 inhibitor candidates. These results will pave the way for the design and optimization of more specific compounds to combat cytokine storm in severe coronavirus patients.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0266632
DOI:
10.1371/journal.pone.0266632.g001
DOI:
10.1371/journal.pone.0266632.g002
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10.1371/journal.pone.0266632.g003
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10.1371/journal.pone.0266632.g004
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10.1371/journal.pone.0266632.g005
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10.1371/journal.pone.0266632.g006
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10.1371/journal.pone.0266632.g007
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10.1371/journal.pone.0266632.g008
DOI:
10.1371/journal.pone.0266632.t001
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10.1371/journal.pone.0266632.t002
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10.1371/journal.pone.0266632.t003
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10.1371/journal.pone.0266632.t004
DOI:
10.1371/journal.pone.0266632.t005
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10.1371/journal.pone.0266632.s001
DOI:
10.1371/journal.pone.0266632.s002
DOI:
10.1371/journal.pone.0266632.s003
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10.1371/journal.pone.0266632.s004
DOI:
10.1371/journal.pone.0266632.s005
DOI:
10.1371/journal.pone.0266632.s006
DOI:
10.1371/journal.pone.0266632.s007
DOI:
10.1371/journal.pone.0266632.s008
DOI:
10.1371/journal.pone.0266632.s009
DOI:
10.1371/journal.pone.0266632.s010
DOI:
10.1371/journal.pone.0266632.s011
DOI:
10.1371/journal.pone.0266632.r001
DOI:
10.1371/journal.pone.0266632.r002
DOI:
10.1371/journal.pone.0266632.r003
DOI:
10.1371/journal.pone.0266632.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2267670-3
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