Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pntd.0000356
Title: Discovery of a non-peptidic inhibitor of West Nile virus NS3 protease by high-throughput docking
Authors: Ekonomiuk D.
Su X.-C.
Ozawa K.
Bodenreider C.
Lim S.P. 
Yin Z.
Keller T.H.
Beer D.
Patel V.
Otting G.
Caflisch A.
Huang D.
Keywords: [4 (carbamimidoylsulfanylmethyl) 2,5 dimethylphenyl]methylsulfanylmethanimidamide
amide
hydrogen
nonstructural protein 3
proteinase
proteinase inhibitor
tryptophan
unclassified drug
(4 (carbamimidoylsulfanylmethyl) 2,5 dimethylphenyl)methylsulfanylmethanimidamide
(4-(carbamimidoylsulfanylmethyl)-2,5-dimethylphenyl)methylsulfanylmethanimidamide
antivirus agent
drug derivative
serine proteinase
serine proteinase inhibitor
thiourea
virus protein
article
binding affinity
binding site
controlled study
drug identification
drug research
enzyme active site
enzyme activity
enzyme assay
fluorescence analysis
high throughput screening
molecular docking
molecular weight
nonhuman
nuclear magnetic resonance spectroscopy
virus infection
West Nile flavivirus
chemical structure
chemistry
drug antagonism
drug effect
enzymology
isolation and purification
metabolism
protein binding
West Nile flavivirus
Antiviral Agents
Models, Molecular
Protein Binding
Serine Proteases
Serine Proteinase Inhibitors
Thiourea
Viral Nonstructural Proteins
West Nile virus
Issue Date: 2009
Citation: Ekonomiuk D., Su X.-C., Ozawa K., Bodenreider C., Lim S.P., Yin Z., Keller T.H., Beer D., Patel V., Otting G., Caflisch A., Huang D. (2009). Discovery of a non-peptidic inhibitor of West Nile virus NS3 protease by high-throughput docking. PLoS Neglected Tropical Diseases 3 (1) : e356. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pntd.0000356
Rights: Attribution 4.0 International
Abstract: Background: The non-structural 3 protease (NS3pro) is an essential flaviviral enzyme and therefore one of the most promising targets for drug development against West Nile virus (WNV) and dengue infections. Methodology: In this work, a small-molecule inhibitor of the WNV NS3pro has been identified by automatic fragment-based docking of about 12000 compounds and testing by nuclear magnetic resonance (NMR) spectroscopy of only 22 molecules. Specific binding of the inhibitor into the active site of NS3pro and its binding mode are confirmed by 15N-HSQC NMR spectra. The inhibitory activity is further validated by an enzymatic assay and a tryptophan fluorescence quenching assay. Conclusion: The inhibitor [4-(carbamimidoylsulfanylmethyl)-2,5-dimethylphenyl]- methylsulfanylmethanimidamide has a good ratio of binding affinity versus molecular weight (ligand efficiency of 0.33 kcal/mol per non-hydrogen atom), and thus has good potential as lead compound for further development to combat West Nile virus infections. © 2009 Ekonomiuk et al.
Source Title: PLoS Neglected Tropical Diseases
URI: https://scholarbank.nus.edu.sg/handle/10635/161675
ISSN: 19352727
DOI: 10.1371/journal.pntd.0000356
Rights: Attribution 4.0 International
Appears in Collections:Elements
Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
10_1371_journal_pntd_0000356.pdf426.98 kBAdobe PDF

OPEN

NoneView/Download

SCOPUSTM   
Citations

66
checked on Sep 25, 2021

Page view(s)

155
checked on Sep 23, 2021

Download(s)

1
checked on Sep 23, 2021

Google ScholarTM

Check

Altmetric


This item is licensed under a Creative Commons License Creative Commons