Potential Coronaviral Inhibitors of the Nucleocapsid Protein Identified In Silico and In Vitro from a Large Natural Product Library

Publication type:
Journal article
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000856621900001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.3390/ph15091046
eISSN
1424-8247
Externe Identifier
  • Clarivate Analytics Document Solution ID: 4R2TM
  • PubMed Identifier: 36145267
Ausgabe der Veröffentlichung
9
Zeitschrift
PHARMACEUTICALS
Schlüsselwörter
  • COVID-19
  • drug discovery
  • microscale thermophoresis
  • natural products
  • nucleocapsid protein
  • virtual drug screening
  • SARS-CoV-2
Artikelnummer
ARTN 1046
Datum der Veröffentlichung
2022
Status
Published
Titel
Potential Coronaviral Inhibitors of the Nucleocapsid Protein Identified In Silico and In Vitro from a Large Natural Product Library
Sub types
  • Article
Ausgabe der Zeitschrift
15

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:p>The nucleocapsid protein (NP) is one of the main proteins out of four structural proteins of coronaviruses including the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, discovered in 2019. NP packages the viral RNA during virus assembly and is, therefore, indispensable for virus reproduction. NP consists of two domains, i.e., the N- and C-terminal domains. RNA-binding is mainly performed by a binding pocket within the N-terminal domain (NTD). NP represents an important target for drug discovery to treat COVID-19. In this project, we used the Vina LC virtual drug screening software and a ZINC-based database with 210,541 natural and naturally derived compounds that specifically target the binding pocket of NTD of NP. Our aim was to identify coronaviral inhibitors that target NP not only of SARS-CoV-2 but also of other diverse human pathogenic coronaviruses. Virtual drug screening and molecular docking procedures resulted in 73 candidate compounds with a binding affinity below −9 kcal/mol with NP NTD of SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-NL63, HoC-229E, and HCoV-HKU1. The top five compounds that met the applied drug-likeness criteria were then tested for their binding in vitro to the NTD of the full-length recombinant NP proteins using microscale thermophoresis. Compounds (1), (2), and (4), which belong to the same scaffold family of 4-oxo-substituted-6-[2-(4a-hydroxy-decahydroisoquinolin-2-yl)2H-chromen-2-ones and which are derivates of coumarin, were bound with good affinity to NP. Compounds (1) and (4) were bound to the full-length NP of SARS-CoV-2 (aa 1–419) with Kd values of 0.798 (±0.02) µM and 8.07 (±0.36) µM, respectively. Then, these coumarin derivatives were tested with the SARS-CoV-2 NP NTD (aa 48–174). Compounds (1) and (4) revealed Kd-values of 0.95 (±0.32) µM and 7.77 (±6.39) µM, respectively. Compounds (1) and (4) caused low toxicity in human A549 and MRC-5 cell lines. These compounds may represent possible drug candidates, which need further optimization to be used against COVID-19 and other coronaviral infections.</jats:p>
Autoren
DOI
10.3390/ph15091046
eISSN
1424-8247
Ausgabe der Veröffentlichung
9
Zeitschrift
Pharmaceuticals
Sprache
en
Online publication date
2022
Paginierung
1046 - 1046
Status
Published online
Herausgeber
MDPI AG
Herausgeber URL
http://dx.doi.org/10.3390/ph15091046
Datum der Datenerfassung
2022
Titel
Potential Coronaviral Inhibitors of the Nucleocapsid Protein Identified In Silico and In Vitro from a Large Natural Product Library
Ausgabe der Zeitschrift
15

Data source: Crossref

Abstract
The nucleocapsid protein (NP) is one of the main proteins out of four structural proteins of coronaviruses including the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, discovered in 2019. NP packages the viral RNA during virus assembly and is, therefore, indispensable for virus reproduction. NP consists of two domains, i.e., the N- and C-terminal domains. RNA-binding is mainly performed by a binding pocket within the N-terminal domain (NTD). NP represents an important target for drug discovery to treat COVID-19. In this project, we used the Vina LC virtual drug screening software and a ZINC-based database with 210,541 natural and naturally derived compounds that specifically target the binding pocket of NTD of NP. Our aim was to identify coronaviral inhibitors that target NP not only of SARS-CoV-2 but also of other diverse human pathogenic coronaviruses. Virtual drug screening and molecular docking procedures resulted in 73 candidate compounds with a binding affinity below -9 kcal/mol with NP NTD of SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-NL63, HoC-229E, and HCoV-HKU1. The top five compounds that met the applied drug-likeness criteria were then tested for their binding in vitro to the NTD of the full-length recombinant NP proteins using microscale thermophoresis. Compounds (<b>1</b>), (<b>2</b>), and (<b>4</b>), which belong to the same scaffold family of 4-oxo-substituted-6-[2-(4a-hydroxy-decahydroisoquinolin-2-yl)2H-chromen-2-ones and which are derivates of coumarin, were bound with good affinity to NP. Compounds (<b>1</b>) and (<b>4</b>) were bound to the full-length NP of SARS-CoV-2 (aa 1-419) with Kd values of 0.798 (±0.02) µM and 8.07 (±0.36) µM, respectively. Then, these coumarin derivatives were tested with the SARS-CoV-2 NP NTD (aa 48-174). Compounds (<b>1</b>) and (<b>4</b>) revealed Kd-values of 0.95 (±0.32) µM and 7.77 (±6.39) µM, respectively. Compounds (<b>1</b>) and (<b>4</b>) caused low toxicity in human A549 and MRC-5 cell lines. These compounds may represent possible drug candidates, which need further optimization to be used against COVID-19 and other coronaviral infections.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Autoren
DOI
10.3390/ph15091046
eISSN
1424-8247
Externe Identifier
  • PubMed Identifier: 36145267
  • PubMed Central ID: PMC9503946
Open access
true
ISSN
1424-8247
Ausgabe der Veröffentlichung
9
Zeitschrift
Pharmaceuticals (Basel, Switzerland)
Sprache
eng
Medium
Electronic
Online publication date
2022
Open access status
Open Access
Paginierung
1046
Datum der Veröffentlichung
2022
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2022
Titel
Potential Coronaviral Inhibitors of the Nucleocapsid Protein Identified In Silico and In Vitro from a Large Natural Product Library.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
15

Files

https://www.mdpi.com/1424-8247/15/9/1046/pdf?version=1661488189 https://europepmc.org/articles/PMC9503946?pdf=render

Data source: Europe PubMed Central

Abstract
The nucleocapsid protein (NP) is one of the main proteins out of four structural proteins of coronaviruses including the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, discovered in 2019. NP packages the viral RNA during virus assembly and is, therefore, indispensable for virus reproduction. NP consists of two domains, i.e., the N- and C-terminal domains. RNA-binding is mainly performed by a binding pocket within the N-terminal domain (NTD). NP represents an important target for drug discovery to treat COVID-19. In this project, we used the Vina LC virtual drug screening software and a ZINC-based database with 210,541 natural and naturally derived compounds that specifically target the binding pocket of NTD of NP. Our aim was to identify coronaviral inhibitors that target NP not only of SARS-CoV-2 but also of other diverse human pathogenic coronaviruses. Virtual drug screening and molecular docking procedures resulted in 73 candidate compounds with a binding affinity below -9 kcal/mol with NP NTD of SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-NL63, HoC-229E, and HCoV-HKU1. The top five compounds that met the applied drug-likeness criteria were then tested for their binding in vitro to the NTD of the full-length recombinant NP proteins using microscale thermophoresis. Compounds (1), (2), and (4), which belong to the same scaffold family of 4-oxo-substituted-6-[2-(4a-hydroxy-decahydroisoquinolin-2-yl)2H-chromen-2-ones and which are derivates of coumarin, were bound with good affinity to NP. Compounds (1) and (4) were bound to the full-length NP of SARS-CoV-2 (aa 1-419) with Kd values of 0.798 (±0.02) µM and 8.07 (±0.36) µM, respectively. Then, these coumarin derivatives were tested with the SARS-CoV-2 NP NTD (aa 48-174). Compounds (1) and (4) revealed Kd-values of 0.95 (±0.32) µM and 7.77 (±6.39) µM, respectively. Compounds (1) and (4) caused low toxicity in human A549 and MRC-5 cell lines. These compounds may represent possible drug candidates, which need further optimization to be used against COVID-19 and other coronaviral infections.
Date of acceptance
2022
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/36145267
DOI
10.3390/ph15091046
Externe Identifier
  • PubMed Central ID: PMC9503946
ISSN
1424-8247
Ausgabe der Veröffentlichung
9
Zeitschrift
Pharmaceuticals (Basel)
Schlüsselwörter
  • COVID-19
  • SARS-CoV-2
  • drug discovery
  • microscale thermophoresis
  • natural products
  • nucleocapsid protein
  • virtual drug screening
Sprache
eng
Country
Switzerland
PII
ph15091046
Datum der Veröffentlichung
2022
Status
Published online
Titel
Potential Coronaviral Inhibitors of the Nucleocapsid Protein Identified In Silico and In Vitro from a Large Natural Product Library.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
15

Data source: PubMed

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