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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 |
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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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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.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0501782</identifier><identifier>PMID: 16250642</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>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</subject><ispartof>Journal of medicinal chemistry, 2005-11, Vol.48 (22), p.6832-6842</ispartof><rights>Copyright © 2005 American Chemical Society</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a478t-104cbba936e8530a219db7f7d0f6eaacfdee67f8bdccbf91ce06df215968da003</citedby><cites>FETCH-LOGICAL-a478t-104cbba936e8530a219db7f7d0f6eaacfdee67f8bdccbf91ce06df215968da003</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17233493$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16250642$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kaeppler, Ulrich</creatorcontrib><creatorcontrib>Stiefl, Nikolaus</creatorcontrib><creatorcontrib>Schiller, Markus</creatorcontrib><creatorcontrib>Vicik, Radim</creatorcontrib><creatorcontrib>Breuning, Alexander</creatorcontrib><creatorcontrib>Schmitz, Werner</creatorcontrib><creatorcontrib>Rupprecht, Daniel</creatorcontrib><creatorcontrib>Schmuck, Carsten</creatorcontrib><creatorcontrib>Baumann, Knut</creatorcontrib><creatorcontrib>Ziebuhr, John</creatorcontrib><creatorcontrib>Schirmeister, Tanja</creatorcontrib><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</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><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.</description><subject>Amides - chemical synthesis</subject><subject>Amides - chemistry</subject><subject>Amides - pharmacology</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Cysteine Endopeptidases</subject><subject>Endopeptidases - chemistry</subject><subject>Ethacrynic Acid - analogs & derivatives</subject><subject>Ethacrynic Acid - chemical synthesis</subject><subject>Ethacrynic Acid - chemistry</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Pharmacology. Drug treatments</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>SARS coronavirus</subject><subject>SARS Virus - enzymology</subject><subject>Structure-Activity Relationship</subject><subject>Viral Proteins - antagonists & inhibitors</subject><subject>Viral Proteins - chemistry</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><recordid>eNqF0c1uEzEQB_AVAtFQOPACyBeQOCzY3u9jlNBSKSmFlAsXa9YeE6dZO7W9afNqPB0bJWouSJxsaX7z12gmSd4y-olRzj6vOlpQVtX8WTJiBadpXtP8eTKilPOUlzw7S16FsKKUZoxnL5MzVvKCljkfJX_G5BofyAxBEe08uXZ2g5tolJFkLKPZYrowEdOp8SgjKnJll6Y10flAnCZxiWSBW_Q46D4i-YFhYzwM9R1Z7KzyrkMycd5Z2BrfBzIHY8mNdxEhIJmaIN2-XZF2R2CQXWssROPsPn4hPaI19jcBq8jUybv9f45x6VR4nbzQsA745vieJz8vvtxOvqazb5dXk_EshbyqY8poLtsWmqzEusgocNaottKVorpEAKkVYlnpulVStrphEmmpNGdFU9YKhpWdJx8OuRvv7nsMUXTD1Lheg0XXB1HWVUYbWv4XsianvOJsgB8PUHoXgkctNt504HeCUbG_qHi66GDfHUP7tkN1kscTDuD9EUCQsNYerDTh5CqeZXmTDS49OBMiPj7Vwd-JssqqQtzeLMTF_LL4_mvCBTvlggxi5XpvhyX_Y8C_t0vGog</recordid><startdate>20051103</startdate><enddate>20051103</enddate><creator>Kaeppler, Ulrich</creator><creator>Stiefl, Nikolaus</creator><creator>Schiller, Markus</creator><creator>Vicik, Radim</creator><creator>Breuning, Alexander</creator><creator>Schmitz, Werner</creator><creator>Rupprecht, Daniel</creator><creator>Schmuck, Carsten</creator><creator>Baumann, Knut</creator><creator>Ziebuhr, John</creator><creator>Schirmeister, Tanja</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20051103</creationdate><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</title><author>Kaeppler, Ulrich ; Stiefl, Nikolaus ; Schiller, Markus ; Vicik, Radim ; Breuning, Alexander ; Schmitz, Werner ; Rupprecht, Daniel ; Schmuck, Carsten ; Baumann, Knut ; Ziebuhr, John ; Schirmeister, Tanja</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a478t-104cbba936e8530a219db7f7d0f6eaacfdee67f8bdccbf91ce06df215968da003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Amides - chemical synthesis</topic><topic>Amides - chemistry</topic><topic>Amides - pharmacology</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Cysteine Endopeptidases</topic><topic>Endopeptidases - chemistry</topic><topic>Ethacrynic Acid - analogs & derivatives</topic><topic>Ethacrynic Acid - chemical synthesis</topic><topic>Ethacrynic Acid - chemistry</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Pharmacology. Drug treatments</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - chemistry</topic><topic>SARS coronavirus</topic><topic>SARS Virus - enzymology</topic><topic>Structure-Activity Relationship</topic><topic>Viral Proteins - antagonists & inhibitors</topic><topic>Viral Proteins - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kaeppler, Ulrich</creatorcontrib><creatorcontrib>Stiefl, Nikolaus</creatorcontrib><creatorcontrib>Schiller, Markus</creatorcontrib><creatorcontrib>Vicik, Radim</creatorcontrib><creatorcontrib>Breuning, Alexander</creatorcontrib><creatorcontrib>Schmitz, Werner</creatorcontrib><creatorcontrib>Rupprecht, Daniel</creatorcontrib><creatorcontrib>Schmuck, Carsten</creatorcontrib><creatorcontrib>Baumann, Knut</creatorcontrib><creatorcontrib>Ziebuhr, John</creatorcontrib><creatorcontrib>Schirmeister, Tanja</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kaeppler, Ulrich</au><au>Stiefl, Nikolaus</au><au>Schiller, Markus</au><au>Vicik, Radim</au><au>Breuning, Alexander</au><au>Schmitz, Werner</au><au>Rupprecht, Daniel</au><au>Schmuck, Carsten</au><au>Baumann, Knut</au><au>Ziebuhr, John</au><au>Schirmeister, Tanja</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2005-11-03</date><risdate>2005</risdate><volume>48</volume><issue>22</issue><spage>6832</spage><epage>6842</epage><pages>6832-6842</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>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.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>16250642</pmid><doi>10.1021/jm0501782</doi><tpages>11</tpages></addata></record> |
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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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