Coronavirus Inhibitors Targeting nsp16

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000930344800001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.3390/molecules28030988
eISSN
1420-3049
Externe Identifier
  • Clarivate Analytics Document Solution ID: 8V0QH
  • PubMed Identifier: 36770656
Ausgabe der Veröffentlichung
3
Zeitschrift
MOLECULES
Schlüsselwörter
  • SARS-CoV-2
  • SARS-CoV-1
  • MERS-CoV
  • nsp16
  • natural products
  • pan-inhibitor
  • virtual drug screening
Artikelnummer
ARTN 988
Datum der Veröffentlichung
2023
Status
Published
Titel
Coronavirus Inhibitors Targeting nsp16
Sub types
  • Article
Ausgabe der Zeitschrift
28

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Abstract
<jats:p>During the past three decades, humans have been confronted with different new coronavirus outbreaks. Since the end of the year 2019, COVID-19 threatens the world as a rapidly spreading infectious disease. For this work, we targeted the non-structural protein 16 (nsp16) as a key protein of SARS-CoV-2, SARS-CoV-1 and MERS-CoV to develop broad-spectrum inhibitors of nsp16. Computational methods were used to filter candidates from a natural product-based library of 224,205 compounds obtained from the ZINC database. The binding of the candidates to nsp16 was assessed using virtual screening with VINA LC, and molecular docking with AutoDock 4.2.6. The top 9 compounds were bound to the nsp16 protein of SARS-CoV-2, SARS-CoV-1, and MERS-CoV with the lowest binding energies (LBEs) in the range of −9.0 to −13.0 kcal with VINA LC. The AutoDock-based LBEs for nsp16 of SARS-CoV-2 ranged from −11.42 to −16.11 kcal/mol with predicted inhibition constants (pKi) from 0.002 to 4.51 nM, the natural substrate S-adenosyl methionine (SAM) was used as control. In silico results were verified by microscale thermophoresis as in vitro assay. The candidates were investigated further for their cytotoxicity in normal MRC-5 lung fibroblasts to determine their therapeutic indices. Here, the IC50 values of all three compounds were &gt;10 µM. In summary, we identified three novel SARS-CoV-2 inhibitors, two of which showed broad-spectrum activity to nsp16 in SARS-CoV-2, SARS-CoV-1, and MERS-CoV. All three compounds are coumarin derivatives that contain chromen-2-one in their scaffolds.</jats:p>
Autoren
DOI
10.3390/molecules28030988
eISSN
1420-3049
Ausgabe der Veröffentlichung
3
Zeitschrift
Molecules
Sprache
en
Online publication date
2023
Paginierung
988 - 988
Status
Published online
Herausgeber
MDPI AG
Herausgeber URL
http://dx.doi.org/10.3390/molecules28030988
Datum der Datenerfassung
2023
Titel
Coronavirus Inhibitors Targeting nsp16
Ausgabe der Zeitschrift
28

Datenquelle: Crossref

Abstract
During the past three decades, humans have been confronted with different new coronavirus outbreaks. Since the end of the year 2019, COVID-19 threatens the world as a rapidly spreading infectious disease. For this work, we targeted the non-structural protein 16 (nsp16) as a key protein of SARS-CoV-2, SARS-CoV-1 and MERS-CoV to develop broad-spectrum inhibitors of nsp16. Computational methods were used to filter candidates from a natural product-based library of 224,205 compounds obtained from the ZINC database. The binding of the candidates to nsp16 was assessed using virtual screening with VINA LC, and molecular docking with AutoDock 4.2.6. The top 9 compounds were bound to the nsp16 protein of SARS-CoV-2, SARS-CoV-1, and MERS-CoV with the lowest binding energies (LBEs) in the range of -9.0 to -13.0 kcal with VINA LC. The AutoDock-based LBEs for nsp16 of SARS-CoV-2 ranged from -11.42 to -16.11 kcal/mol with predicted inhibition constants (pKi) from 0.002 to 4.51 nM, the natural substrate S-adenosyl methionine (SAM) was used as control. In silico results were verified by microscale thermophoresis as in vitro assay. The candidates were investigated further for their cytotoxicity in normal MRC-5 lung fibroblasts to determine their therapeutic indices. Here, the IC<sub>50</sub> values of all three compounds were >10 µM. In summary, we identified three novel SARS-CoV-2 inhibitors, two of which showed broad-spectrum activity to nsp16 in SARS-CoV-2, SARS-CoV-1, and MERS-CoV. All three compounds are coumarin derivatives that contain chromen-2-one in their scaffolds.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Autoren
DOI
10.3390/molecules28030988
eISSN
1420-3049
Externe Identifier
  • PubMed Identifier: 36770656
  • PubMed Central ID: PMC9920298
Funding acknowledgements
  • Frankfurt a. M.:
  • Marc Strobel:
  • CVC Capital Partners:
Open access
true
ISSN
1420-3049
Ausgabe der Veröffentlichung
3
Zeitschrift
Molecules (Basel, Switzerland)
Schlüsselwörter
  • Humans
  • S-Adenosylmethionine
  • Molecular Docking Simulation
  • Middle East Respiratory Syndrome Coronavirus
  • COVID-19
  • SARS-CoV-2
Sprache
eng
Medium
Electronic
Online publication date
2023
Open access status
Open Access
Paginierung
988
Datum der Veröffentlichung
2023
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2023
Titel
Coronavirus Inhibitors Targeting nsp16.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
28

Files

https://www.mdpi.com/1420-3049/28/3/988/pdf?version=1675222239 https://europepmc.org/articles/PMC9920298?pdf=render

Datenquelle: Europe PubMed Central

Abstract
During the past three decades, humans have been confronted with different new coronavirus outbreaks. Since the end of the year 2019, COVID-19 threatens the world as a rapidly spreading infectious disease. For this work, we targeted the non-structural protein 16 (nsp16) as a key protein of SARS-CoV-2, SARS-CoV-1 and MERS-CoV to develop broad-spectrum inhibitors of nsp16. Computational methods were used to filter candidates from a natural product-based library of 224,205 compounds obtained from the ZINC database. The binding of the candidates to nsp16 was assessed using virtual screening with VINA LC, and molecular docking with AutoDock 4.2.6. The top 9 compounds were bound to the nsp16 protein of SARS-CoV-2, SARS-CoV-1, and MERS-CoV with the lowest binding energies (LBEs) in the range of -9.0 to -13.0 kcal with VINA LC. The AutoDock-based LBEs for nsp16 of SARS-CoV-2 ranged from -11.42 to -16.11 kcal/mol with predicted inhibition constants (pKi) from 0.002 to 4.51 nM, the natural substrate S-adenosyl methionine (SAM) was used as control. In silico results were verified by microscale thermophoresis as in vitro assay. The candidates were investigated further for their cytotoxicity in normal MRC-5 lung fibroblasts to determine their therapeutic indices. Here, the IC50 values of all three compounds were >10 µM. In summary, we identified three novel SARS-CoV-2 inhibitors, two of which showed broad-spectrum activity to nsp16 in SARS-CoV-2, SARS-CoV-1, and MERS-CoV. All three compounds are coumarin derivatives that contain chromen-2-one in their scaffolds.
Date of acceptance
2023
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/36770656
DOI
10.3390/molecules28030988
eISSN
1420-3049
Externe Identifier
  • PubMed Central ID: PMC9920298
Ausgabe der Veröffentlichung
3
Zeitschrift
Molecules
Schlüsselwörter
  • MERS-CoV
  • SARS-CoV-1
  • SARS-CoV-2
  • natural products
  • nsp16
  • pan-inhibitor
  • virtual drug screening
  • Humans
  • COVID-19
  • SARS-CoV-2
  • Molecular Docking Simulation
  • Middle East Respiratory Syndrome Coronavirus
  • S-Adenosylmethionine
Sprache
eng
Country
Switzerland
PII
molecules28030988
Datum der Veröffentlichung
2023
Status
Published online
Datum, an dem der Datensatz öffentlich gemacht wurde
2023
Titel
Coronavirus Inhibitors Targeting nsp16.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
28

Datenquelle: PubMed

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