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A New Lead for Nonpeptidic Active-Site-Directed Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus Main Protease Discovered by a Combination of Screening and Docking Methods

The coronavirus main protease, Mpro, is considered to be a major target for drugs suitable for combating coronavirus infections including severe acute respiratory syndrome (SARS). An HPLC-based screening of electrophilic compounds that was performed to identify potential Mpro inhibitors revealed eta...

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Published in:Journal of medicinal chemistry 2005-11, Vol.48 (22), p.6832-6842
Main Authors: Kaeppler, Ulrich, Stiefl, Nikolaus, Schiller, Markus, Vicik, Radim, Breuning, Alexander, Schmitz, Werner, Rupprecht, Daniel, Schmuck, Carsten, Baumann, Knut, Ziebuhr, John, Schirmeister, Tanja
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cited_by cdi_FETCH-LOGICAL-a478t-104cbba936e8530a219db7f7d0f6eaacfdee67f8bdccbf91ce06df215968da003
cites cdi_FETCH-LOGICAL-a478t-104cbba936e8530a219db7f7d0f6eaacfdee67f8bdccbf91ce06df215968da003
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container_issue 22
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container_title Journal of medicinal chemistry
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creator Kaeppler, Ulrich
Stiefl, Nikolaus
Schiller, Markus
Vicik, Radim
Breuning, Alexander
Schmitz, Werner
Rupprecht, Daniel
Schmuck, Carsten
Baumann, Knut
Ziebuhr, John
Schirmeister, Tanja
description The coronavirus main protease, Mpro, is considered to be a major target for drugs suitable for combating coronavirus infections including severe acute respiratory syndrome (SARS). An HPLC-based screening of electrophilic compounds that was performed to identify potential Mpro inhibitors revealed etacrynic acid tert-butylamide (6a) as an effective nonpeptidic inhibitor. Docking studies suggested a binding mode in which the phenyl ring acts as a spacer bridging the inhibitor's activated double bond and its hydrophobic tert-butyl moiety. The latter is supposed to fit into the S4 pocket of the target protease. Furthermore, these studies revealed etacrynic acid amide (6b) as a promising lead for nonpeptidic active-site-directed Mpro inhibitors. In a fluorimetric enzyme assay using a novel fluorescence resonance energy transfer (FRET) pair labeled substrate, compound 6b showed a K i value of 35.3 μM. Since the novel lead compound does not target the S1‘, S1, and S2 subsites of the enzyme's substrate-binding pockets, there is room for improvement that underlines the lead character of compound 6b.
doi_str_mv 10.1021/jm0501782
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ispartof Journal of medicinal chemistry, 2005-11, Vol.48 (22), p.6832-6842
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source American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list)
subjects Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Binding Sites
Biological and medical sciences
Chromatography, High Pressure Liquid
Cysteine Endopeptidases
Endopeptidases - chemistry
Ethacrynic Acid - analogs & derivatives
Ethacrynic Acid - chemical synthesis
Ethacrynic Acid - chemistry
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Protease Inhibitors - chemical synthesis
Protease Inhibitors - chemistry
SARS coronavirus
SARS Virus - enzymology
Structure-Activity Relationship
Viral Proteins - antagonists & inhibitors
Viral Proteins - chemistry
title A New Lead for Nonpeptidic Active-Site-Directed Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus Main Protease Discovered by a Combination of Screening and Docking Methods
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