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Quantitative structure-activity relationships, molecular docking and molecular dynamics simulations reveal drug repurposing candidates as potent SARS-CoV-2 main protease inhibitors
The current outbreak of COVID-19 is leading an unprecedented scientific effort focusing on targeting SARS-CoV-2 proteins critical for its viral replication. Herein, we performed high-throughput virtual screening of more than eleven thousand FDA-approved drugs using backpropagation-based artificial n...
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Published in: | Journal of biomolecular structure & dynamics 2022-01, Vol.40 (21), p.11339-11356 |
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description | The current outbreak of COVID-19 is leading an unprecedented scientific effort focusing on targeting SARS-CoV-2 proteins critical for its viral replication. Herein, we performed high-throughput virtual screening of more than eleven thousand FDA-approved drugs using backpropagation-based artificial neural networks (q
2
LOO
= 0.60, r
2
= 0.80 and r
2
pred
= 0.91), partial-least-square (PLS) regression (q
2
LOO
= 0.83, r
2
= 0.62 and r
2
pred
= 0.70) and sequential minimal optimization (SMO) regression (q
2
LOO
= 0.70, r
2
= 0.80 and r
2
pred
= 0.89). We simulated the stability of Acarbose-derived hexasaccharide, Naratriptan, Peramivir, Dihydrostreptomycin, Enviomycin, Rolitetracycline, Viomycin, Angiotensin II, Angiotensin 1-7, Angiotensinamide, Fenoterol, Zanamivir, Laninamivir and Laninamivir octanoate with 3CL
pro
by 100 ns and calculated binding free energy using molecular mechanics combined with Poisson-Boltzmann surface area (MM-PBSA). Our QSAR models and molecular dynamics data suggest that seven repurposed-drug candidates such as Acarbose-derived Hexasaccharide, Angiotensinamide, Dihydrostreptomycin, Enviomycin, Fenoterol, Naratriptan and Viomycin are potential SARS-CoV-2 main protease inhibitors. In addition, our QSAR models and molecular dynamics simulations revealed that His41, Asn142, Cys145, Glu166 and Gln189 are potential pharmacophoric centers for 3CL
pro
inhibitors. Glu166 is a potential pharmacophore for drug design and inhibitors that interact with this residue may be critical to avoid dimerization of 3CL
pro
. Our results will contribute to future investigations of novel chemical scaffolds and the discovery of novel hits in high-throughput screening as potential anti-SARS-CoV-2 properties.
Communicated by Ramaswamy H. Sarma |
doi_str_mv | 10.1080/07391102.2021.1958700 |
format | article |
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2
LOO
= 0.60, r
2
= 0.80 and r
2
pred
= 0.91), partial-least-square (PLS) regression (q
2
LOO
= 0.83, r
2
= 0.62 and r
2
pred
= 0.70) and sequential minimal optimization (SMO) regression (q
2
LOO
= 0.70, r
2
= 0.80 and r
2
pred
= 0.89). We simulated the stability of Acarbose-derived hexasaccharide, Naratriptan, Peramivir, Dihydrostreptomycin, Enviomycin, Rolitetracycline, Viomycin, Angiotensin II, Angiotensin 1-7, Angiotensinamide, Fenoterol, Zanamivir, Laninamivir and Laninamivir octanoate with 3CL
pro
by 100 ns and calculated binding free energy using molecular mechanics combined with Poisson-Boltzmann surface area (MM-PBSA). Our QSAR models and molecular dynamics data suggest that seven repurposed-drug candidates such as Acarbose-derived Hexasaccharide, Angiotensinamide, Dihydrostreptomycin, Enviomycin, Fenoterol, Naratriptan and Viomycin are potential SARS-CoV-2 main protease inhibitors. In addition, our QSAR models and molecular dynamics simulations revealed that His41, Asn142, Cys145, Glu166 and Gln189 are potential pharmacophoric centers for 3CL
pro
inhibitors. Glu166 is a potential pharmacophore for drug design and inhibitors that interact with this residue may be critical to avoid dimerization of 3CL
pro
. Our results will contribute to future investigations of novel chemical scaffolds and the discovery of novel hits in high-throughput screening as potential anti-SARS-CoV-2 properties.
Communicated by Ramaswamy H. Sarma</description><identifier>ISSN: 0739-1102</identifier><identifier>EISSN: 1538-0254</identifier><identifier>DOI: 10.1080/07391102.2021.1958700</identifier><identifier>PMID: 34370631</identifier><language>eng</language><publisher>England: Taylor & Francis</publisher><subject>Acarbose ; Angiotensin Amide ; Antiviral Agents - pharmacology ; Dihydrostreptomycin Sulfate ; Drug Repositioning ; Enviomycin ; Fenoterol ; high-throughput virtual screening ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; molecular dynamics simulations ; prediction ; Protease Inhibitors - pharmacology ; QSAR models ; Quantitative Structure-Activity Relationship ; SARS-CoV-2 ; SARS-CoV-2 - drug effects</subject><ispartof>Journal of biomolecular structure & dynamics, 2022-01, Vol.40 (21), p.11339-11356</ispartof><rights>2021 Informa UK Limited, trading as Taylor & Francis Group 2021</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c366t-b71956c492ba535a52ba8a6557fa9d6d880ab8fd7d500771255b06a80769d0b93</citedby><cites>FETCH-LOGICAL-c366t-b71956c492ba535a52ba8a6557fa9d6d880ab8fd7d500771255b06a80769d0b93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34370631$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>de Souza, Anacleto Silva</creatorcontrib><creatorcontrib>de Souza, Robson Francisco</creatorcontrib><creatorcontrib>Guzzo, Cristiane Rodrigues</creatorcontrib><title>Quantitative structure-activity relationships, molecular docking and molecular dynamics simulations reveal drug repurposing candidates as potent SARS-CoV-2 main protease inhibitors</title><title>Journal of biomolecular structure & dynamics</title><addtitle>J Biomol Struct Dyn</addtitle><description>The current outbreak of COVID-19 is leading an unprecedented scientific effort focusing on targeting SARS-CoV-2 proteins critical for its viral replication. Herein, we performed high-throughput virtual screening of more than eleven thousand FDA-approved drugs using backpropagation-based artificial neural networks (q
2
LOO
= 0.60, r
2
= 0.80 and r
2
pred
= 0.91), partial-least-square (PLS) regression (q
2
LOO
= 0.83, r
2
= 0.62 and r
2
pred
= 0.70) and sequential minimal optimization (SMO) regression (q
2
LOO
= 0.70, r
2
= 0.80 and r
2
pred
= 0.89). We simulated the stability of Acarbose-derived hexasaccharide, Naratriptan, Peramivir, Dihydrostreptomycin, Enviomycin, Rolitetracycline, Viomycin, Angiotensin II, Angiotensin 1-7, Angiotensinamide, Fenoterol, Zanamivir, Laninamivir and Laninamivir octanoate with 3CL
pro
by 100 ns and calculated binding free energy using molecular mechanics combined with Poisson-Boltzmann surface area (MM-PBSA). Our QSAR models and molecular dynamics data suggest that seven repurposed-drug candidates such as Acarbose-derived Hexasaccharide, Angiotensinamide, Dihydrostreptomycin, Enviomycin, Fenoterol, Naratriptan and Viomycin are potential SARS-CoV-2 main protease inhibitors. In addition, our QSAR models and molecular dynamics simulations revealed that His41, Asn142, Cys145, Glu166 and Gln189 are potential pharmacophoric centers for 3CL
pro
inhibitors. Glu166 is a potential pharmacophore for drug design and inhibitors that interact with this residue may be critical to avoid dimerization of 3CL
pro
. Our results will contribute to future investigations of novel chemical scaffolds and the discovery of novel hits in high-throughput screening as potential anti-SARS-CoV-2 properties.
Communicated by Ramaswamy H. Sarma</description><subject>Acarbose</subject><subject>Angiotensin Amide</subject><subject>Antiviral Agents - pharmacology</subject><subject>Dihydrostreptomycin Sulfate</subject><subject>Drug Repositioning</subject><subject>Enviomycin</subject><subject>Fenoterol</subject><subject>high-throughput virtual screening</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Dynamics Simulation</subject><subject>molecular dynamics simulations</subject><subject>prediction</subject><subject>Protease Inhibitors - pharmacology</subject><subject>QSAR models</subject><subject>Quantitative Structure-Activity Relationship</subject><subject>SARS-CoV-2</subject><subject>SARS-CoV-2 - drug effects</subject><issn>0739-1102</issn><issn>1538-0254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kU1v1DAQhiMEokvhJ4B85ECWcbK2kxvVqnxIlRAUuFoT22kNiR38UbT_ix-Io90iTpzGGj_PjOW3qp5T2FLo4DWItqcUmm0DDd3SnnUC4EG1oaztamjY7mG1WZl6hc6qJzF-h0JSQR9XZ-2uFcBbuql-f8rokk2Y7J0hMYWsUg6mRlUaNh1IMFO58y7e2iW-IrOfjMoTBqK9-mHdDUGn_-0eHM5WRRLtnE9mmXFncCI65JtyXnJYfFxVVVyrMZlIMJLFJ-MSub74fF3v_be6ITNaR5ZQ-hgNse7WDjb5EJ9Wj0aconl2qufV17eXX_bv66uP7z7sL65q1XKe6kGUb-Fq1zcDspYhK7VDzpgYsddcdx3g0I1aaAYgBG0YG4BjB4L3Goa-Pa9eHueWN_zMJiY526jMNKEzPkfZMA7AefEKyo6oCj7GYEa5BDtjOEgKcg1M3gcm18DkKbDivTityMNs9F_rPqECvDkC1o0-zPjLh0nLhIfJhzGgUzbK9v87_gAUzamW</recordid><startdate>20220101</startdate><enddate>20220101</enddate><creator>de Souza, Anacleto Silva</creator><creator>de Souza, Robson Francisco</creator><creator>Guzzo, Cristiane Rodrigues</creator><general>Taylor & Francis</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></search><sort><creationdate>20220101</creationdate><title>Quantitative structure-activity relationships, molecular docking and molecular dynamics simulations reveal drug repurposing candidates as potent SARS-CoV-2 main protease inhibitors</title><author>de Souza, Anacleto Silva ; de Souza, Robson Francisco ; Guzzo, Cristiane Rodrigues</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c366t-b71956c492ba535a52ba8a6557fa9d6d880ab8fd7d500771255b06a80769d0b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Acarbose</topic><topic>Angiotensin Amide</topic><topic>Antiviral Agents - pharmacology</topic><topic>Dihydrostreptomycin Sulfate</topic><topic>Drug Repositioning</topic><topic>Enviomycin</topic><topic>Fenoterol</topic><topic>high-throughput virtual screening</topic><topic>Molecular Docking Simulation</topic><topic>Molecular Dynamics Simulation</topic><topic>molecular dynamics simulations</topic><topic>prediction</topic><topic>Protease Inhibitors - pharmacology</topic><topic>QSAR models</topic><topic>Quantitative Structure-Activity Relationship</topic><topic>SARS-CoV-2</topic><topic>SARS-CoV-2 - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>de Souza, Anacleto Silva</creatorcontrib><creatorcontrib>de Souza, Robson Francisco</creatorcontrib><creatorcontrib>Guzzo, Cristiane Rodrigues</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><jtitle>Journal of biomolecular structure & dynamics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>de Souza, Anacleto Silva</au><au>de Souza, Robson Francisco</au><au>Guzzo, Cristiane Rodrigues</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Quantitative structure-activity relationships, molecular docking and molecular dynamics simulations reveal drug repurposing candidates as potent SARS-CoV-2 main protease inhibitors</atitle><jtitle>Journal of biomolecular structure & dynamics</jtitle><addtitle>J Biomol Struct Dyn</addtitle><date>2022-01-01</date><risdate>2022</risdate><volume>40</volume><issue>21</issue><spage>11339</spage><epage>11356</epage><pages>11339-11356</pages><issn>0739-1102</issn><eissn>1538-0254</eissn><abstract>The current outbreak of COVID-19 is leading an unprecedented scientific effort focusing on targeting SARS-CoV-2 proteins critical for its viral replication. Herein, we performed high-throughput virtual screening of more than eleven thousand FDA-approved drugs using backpropagation-based artificial neural networks (q
2
LOO
= 0.60, r
2
= 0.80 and r
2
pred
= 0.91), partial-least-square (PLS) regression (q
2
LOO
= 0.83, r
2
= 0.62 and r
2
pred
= 0.70) and sequential minimal optimization (SMO) regression (q
2
LOO
= 0.70, r
2
= 0.80 and r
2
pred
= 0.89). We simulated the stability of Acarbose-derived hexasaccharide, Naratriptan, Peramivir, Dihydrostreptomycin, Enviomycin, Rolitetracycline, Viomycin, Angiotensin II, Angiotensin 1-7, Angiotensinamide, Fenoterol, Zanamivir, Laninamivir and Laninamivir octanoate with 3CL
pro
by 100 ns and calculated binding free energy using molecular mechanics combined with Poisson-Boltzmann surface area (MM-PBSA). Our QSAR models and molecular dynamics data suggest that seven repurposed-drug candidates such as Acarbose-derived Hexasaccharide, Angiotensinamide, Dihydrostreptomycin, Enviomycin, Fenoterol, Naratriptan and Viomycin are potential SARS-CoV-2 main protease inhibitors. In addition, our QSAR models and molecular dynamics simulations revealed that His41, Asn142, Cys145, Glu166 and Gln189 are potential pharmacophoric centers for 3CL
pro
inhibitors. Glu166 is a potential pharmacophore for drug design and inhibitors that interact with this residue may be critical to avoid dimerization of 3CL
pro
. Our results will contribute to future investigations of novel chemical scaffolds and the discovery of novel hits in high-throughput screening as potential anti-SARS-CoV-2 properties.
Communicated by Ramaswamy H. Sarma</abstract><cop>England</cop><pub>Taylor & Francis</pub><pmid>34370631</pmid><doi>10.1080/07391102.2021.1958700</doi><tpages>18</tpages></addata></record> |
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source | Taylor and Francis Science and Technology Collection |
subjects | Acarbose Angiotensin Amide Antiviral Agents - pharmacology Dihydrostreptomycin Sulfate Drug Repositioning Enviomycin Fenoterol high-throughput virtual screening Molecular Docking Simulation Molecular Dynamics Simulation molecular dynamics simulations prediction Protease Inhibitors - pharmacology QSAR models Quantitative Structure-Activity Relationship SARS-CoV-2 SARS-CoV-2 - drug effects |
title | Quantitative structure-activity relationships, molecular docking and molecular dynamics simulations reveal drug repurposing candidates as potent SARS-CoV-2 main protease inhibitors |
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