Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV
The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds...
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| Veröffentlicht in: | Antiviral research 2023-08, Vol.216, p.105653, Article 105653 |
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| creator | Chang, Yu-Jen Le, Uyen Nguyen Phuong Liu, Jia-Jun Li, Sin-Rong Chao, Shao-Ting Lai, Hsueh-Chou Lin, Yu-Feng Hsu, Kai-Cheng Lu, Chih-Hao Lin, Cheng-Wen |
| description | The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 Mpro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 Mpro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 Mpro enzymatic activity, with a half maximal inhibitory concentration (IC50) of 2.69 μM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. Mpro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 Mpro enzymatic activity, with an IC50 of 3.05 μM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC50 of 74.35.•C1 structural analogs NSC89641 and NSC96435 also inhibited MERS-CoV Mpro, with IC50 values of |
| doi_str_mv | 10.1016/j.antiviral.2023.105653 |
| format | Article |
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•In-silico screening predicted potential SARS-CoV-2 Mpro inhibitors among compounds in the US NCI database.•Compound NSC89640 (coded as C1) strongly inhibited Mpro-mediated cleavage activity.•C1 showed strong inhibitory activity against SARS-CoV-2 Mpro, with an IC50 of 2.69 μM and a SI of >74.35.•C1 structural analogs NSC89641 and NSC96435 also inhibited MERS-CoV Mpro, with IC50 values of <3.5 μM.•C1 shows potential as an effective Mpro inhibitor for use as a broad-spectrum agent against COVID-19 and MERS-CoV.</description><identifier>ISSN: 0166-3542</identifier><identifier>ISSN: 1872-9096</identifier><identifier>EISSN: 1872-9096</identifier><identifier>DOI: 10.1016/j.antiviral.2023.105653</identifier><identifier>PMID: 37321487</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; cis-/trans-cleavage assay ; COVID-19 ; Cysteine Endopeptidases - chemistry ; Humans ; In-silico prediction ; Main protease ; MERS-CoV ; Middle East Respiratory Syndrome Coronavirus ; Molecular Docking Simulation ; National cancer institute database ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; SARS-CoV-2</subject><ispartof>Antiviral research, 2023-08, Vol.216, p.105653, Article 105653</ispartof><rights>2023 Elsevier B.V.</rights><rights>Copyright © 2023 Elsevier B.V. All rights reserved.</rights><rights>2023 Elsevier B.V. All rights reserved. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-b0a8137b05900171d0d812f697ea741e2515c88ea47ccc4ccaad7391f0337aba3</citedby><cites>FETCH-LOGICAL-c476t-b0a8137b05900171d0d812f697ea741e2515c88ea47ccc4ccaad7391f0337aba3</cites><orcidid>0000-0003-1998-3310 ; 0000-0002-1661-7553 ; 0000-0002-8363-6244</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.antiviral.2023.105653$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37321487$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chang, Yu-Jen</creatorcontrib><creatorcontrib>Le, Uyen Nguyen Phuong</creatorcontrib><creatorcontrib>Liu, Jia-Jun</creatorcontrib><creatorcontrib>Li, Sin-Rong</creatorcontrib><creatorcontrib>Chao, Shao-Ting</creatorcontrib><creatorcontrib>Lai, Hsueh-Chou</creatorcontrib><creatorcontrib>Lin, Yu-Feng</creatorcontrib><creatorcontrib>Hsu, Kai-Cheng</creatorcontrib><creatorcontrib>Lu, Chih-Hao</creatorcontrib><creatorcontrib>Lin, Cheng-Wen</creatorcontrib><title>Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV</title><title>Antiviral research</title><addtitle>Antiviral Res</addtitle><description>The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 Mpro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 Mpro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 Mpro enzymatic activity, with a half maximal inhibitory concentration (IC50) of 2.69 μM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. Mpro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 Mpro enzymatic activity, with an IC50 of 3.05 μM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC50 of <3.5 μM. Thus, C1 shows potential as an effective Mpro inhibitor of SARS-CoV-2 and MERS-CoV. Our rigorous study framework efficiently identified lead compounds targeting the SARS-CoV-2 Mpro and MERS-CoV Mpro.
•In-silico screening predicted potential SARS-CoV-2 Mpro inhibitors among compounds in the US NCI database.•Compound NSC89640 (coded as C1) strongly inhibited Mpro-mediated cleavage activity.•C1 showed strong inhibitory activity against SARS-CoV-2 Mpro, with an IC50 of 2.69 μM and a SI of >74.35.•C1 structural analogs NSC89641 and NSC96435 also inhibited MERS-CoV Mpro, with IC50 values of <3.5 μM.•C1 shows potential as an effective Mpro inhibitor for use as a broad-spectrum agent against COVID-19 and MERS-CoV.</description><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>cis-/trans-cleavage assay</subject><subject>COVID-19</subject><subject>Cysteine Endopeptidases - chemistry</subject><subject>Humans</subject><subject>In-silico prediction</subject><subject>Main protease</subject><subject>MERS-CoV</subject><subject>Middle East Respiratory Syndrome Coronavirus</subject><subject>Molecular Docking Simulation</subject><subject>National cancer institute database</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacology</subject><subject>SARS-CoV-2</subject><issn>0166-3542</issn><issn>1872-9096</issn><issn>1872-9096</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2P1DAMhisEYoeFvwA5cslskn6kPaHRaPmQFiGxwDVyU3cmozYZkrSr4T_xH8nSZQQnTpbt168tP1n2irM1Z7y6OqzBRjMbD8NaMJGnalmV-aNsxWspaMOa6nG2SsqK5mUhLrJnIRwYY5Vs6qfZRS5zwYtarrKfWze2xhq7I8ktTjCQoD3i78qdiXuiTaBX0YMNVA8IM-yQoP1xGiEaTSAEOAWCfY86HYTDiXicEYZAWu-go-GYGn4aibF705rofCBxD5FE8DtMYY9kBGPJ0buIEDAQ15PbzedbunXfqCBgO_LxekmfZ0_6ZI0vHuJl9vXt9Zfte3rz6d2H7eaG6kJWkbYMap7LlpUNY1zyjnU1F33VSARZcBQlL3VdIxRSa11oDdDJvOE9y3MJLeSX2ZvF9zi1I3YabXrAoI7ejOBPyoFR_3as2audmxVnoip4JZPD6wcH775PGKIaTdA4DGDRTUGJWkhR1o2sk1QuUu1dCB778x7O1D1tdVBn2uqetlpop8mXf595nvuDNwk2iwDTs2aDXgVt0GrsjE9YVOfMf5f8AkbvxGs</recordid><startdate>20230801</startdate><enddate>20230801</enddate><creator>Chang, Yu-Jen</creator><creator>Le, Uyen Nguyen Phuong</creator><creator>Liu, Jia-Jun</creator><creator>Li, Sin-Rong</creator><creator>Chao, Shao-Ting</creator><creator>Lai, Hsueh-Chou</creator><creator>Lin, Yu-Feng</creator><creator>Hsu, Kai-Cheng</creator><creator>Lu, Chih-Hao</creator><creator>Lin, Cheng-Wen</creator><general>Elsevier B.V</general><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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1998-3310</orcidid><orcidid>https://orcid.org/0000-0002-1661-7553</orcidid><orcidid>https://orcid.org/0000-0002-8363-6244</orcidid></search><sort><creationdate>20230801</creationdate><title>Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV</title><author>Chang, Yu-Jen ; Le, Uyen Nguyen Phuong ; Liu, Jia-Jun ; Li, Sin-Rong ; Chao, Shao-Ting ; Lai, Hsueh-Chou ; Lin, Yu-Feng ; Hsu, Kai-Cheng ; Lu, Chih-Hao ; Lin, Cheng-Wen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c476t-b0a8137b05900171d0d812f697ea741e2515c88ea47ccc4ccaad7391f0337aba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>cis-/trans-cleavage assay</topic><topic>COVID-19</topic><topic>Cysteine Endopeptidases - chemistry</topic><topic>Humans</topic><topic>In-silico prediction</topic><topic>Main protease</topic><topic>MERS-CoV</topic><topic>Middle East Respiratory Syndrome Coronavirus</topic><topic>Molecular Docking Simulation</topic><topic>National cancer institute database</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - pharmacology</topic><topic>SARS-CoV-2</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chang, Yu-Jen</creatorcontrib><creatorcontrib>Le, Uyen Nguyen Phuong</creatorcontrib><creatorcontrib>Liu, Jia-Jun</creatorcontrib><creatorcontrib>Li, Sin-Rong</creatorcontrib><creatorcontrib>Chao, Shao-Ting</creatorcontrib><creatorcontrib>Lai, Hsueh-Chou</creatorcontrib><creatorcontrib>Lin, Yu-Feng</creatorcontrib><creatorcontrib>Hsu, Kai-Cheng</creatorcontrib><creatorcontrib>Lu, Chih-Hao</creatorcontrib><creatorcontrib>Lin, Cheng-Wen</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Antiviral research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chang, Yu-Jen</au><au>Le, Uyen Nguyen Phuong</au><au>Liu, Jia-Jun</au><au>Li, Sin-Rong</au><au>Chao, Shao-Ting</au><au>Lai, Hsueh-Chou</au><au>Lin, Yu-Feng</au><au>Hsu, Kai-Cheng</au><au>Lu, Chih-Hao</au><au>Lin, Cheng-Wen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV</atitle><jtitle>Antiviral research</jtitle><addtitle>Antiviral Res</addtitle><date>2023-08-01</date><risdate>2023</risdate><volume>216</volume><spage>105653</spage><pages>105653-</pages><artnum>105653</artnum><issn>0166-3542</issn><issn>1872-9096</issn><eissn>1872-9096</eissn><abstract>The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 Mpro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 Mpro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 Mpro enzymatic activity, with a half maximal inhibitory concentration (IC50) of 2.69 μM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. Mpro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 Mpro enzymatic activity, with an IC50 of 3.05 μM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC50 of <3.5 μM. Thus, C1 shows potential as an effective Mpro inhibitor of SARS-CoV-2 and MERS-CoV. Our rigorous study framework efficiently identified lead compounds targeting the SARS-CoV-2 Mpro and MERS-CoV Mpro.
•In-silico screening predicted potential SARS-CoV-2 Mpro inhibitors among compounds in the US NCI database.•Compound NSC89640 (coded as C1) strongly inhibited Mpro-mediated cleavage activity.•C1 showed strong inhibitory activity against SARS-CoV-2 Mpro, with an IC50 of 2.69 μM and a SI of >74.35.•C1 structural analogs NSC89641 and NSC96435 also inhibited MERS-CoV Mpro, with IC50 values of <3.5 μM.•C1 shows potential as an effective Mpro inhibitor for use as a broad-spectrum agent against COVID-19 and MERS-CoV.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>37321487</pmid><doi>10.1016/j.antiviral.2023.105653</doi><orcidid>https://orcid.org/0000-0003-1998-3310</orcidid><orcidid>https://orcid.org/0000-0002-1661-7553</orcidid><orcidid>https://orcid.org/0000-0002-8363-6244</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Antiviral research, 2023-08, Vol.216, p.105653, Article 105653 |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Antiviral Agents - chemistry Antiviral Agents - pharmacology cis-/trans-cleavage assay COVID-19 Cysteine Endopeptidases - chemistry Humans In-silico prediction Main protease MERS-CoV Middle East Respiratory Syndrome Coronavirus Molecular Docking Simulation National cancer institute database Protease Inhibitors - chemistry Protease Inhibitors - pharmacology SARS-CoV-2 |
| title | Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV |
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