Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates
Identifieur interne : 000074 ( Pmc/Checkpoint ); précédent : 000073; suivant : 000075Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates
Auteurs : Yu Wai Chen [Hong Kong] ; Chin-Pang Bennu Yiu [Hong Kong] ; Kwok-Yin Wong [Hong Kong]Source :
- F1000Research [ 2046-1402 ] ; 2020.
Abstract
We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL pro) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart. With the 3CL pro molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache. The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.
Url:
DOI: 10.12688/f1000research.22457.1
PubMed: 32194944
PubMed Central: 7062204
Affiliations:
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<sup>pro</sup>) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates</title><author><name sortKey="Chen, Yu Wai" sort="Chen, Yu Wai" uniqKey="Chen Y" first="Yu Wai" last="Chen">Yu Wai Chen</name><affiliation wicri:level="1"><nlm:aff id="a1">Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hunghom, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hunghom</wicri:regionArea><wicri:noRegion>Hunghom</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="a2">State Key Laboratory of Chemical Biology and Drug Discovery, Hunghom, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>State Key Laboratory of Chemical Biology and Drug Discovery, Hunghom</wicri:regionArea><wicri:noRegion>Hunghom</wicri:noRegion></affiliation></author><author><name sortKey="Yiu, Chin Pang Bennu" sort="Yiu, Chin Pang Bennu" uniqKey="Yiu C" first="Chin-Pang Bennu" last="Yiu">Chin-Pang Bennu Yiu</name><affiliation wicri:level="1"><nlm:aff id="a3">Independent Researcher, La Costa, Ma On Shan, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>Independent Researcher, La Costa, Ma On Shan</wicri:regionArea><wicri:noRegion>Ma On Shan</wicri:noRegion></affiliation></author><author><name sortKey="Wong, Kwok Yin" sort="Wong, Kwok Yin" uniqKey="Wong K" first="Kwok-Yin" last="Wong">Kwok-Yin Wong</name><affiliation wicri:level="1"><nlm:aff id="a1">Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hunghom, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hunghom</wicri:regionArea><wicri:noRegion>Hunghom</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="a2">State Key Laboratory of Chemical Biology and Drug Discovery, Hunghom, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>State Key Laboratory of Chemical Biology and Drug Discovery, Hunghom</wicri:regionArea><wicri:noRegion>Hunghom</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32194944</idno><idno type="pmc">7062204</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062204</idno><idno type="RBID">PMC:7062204</idno><idno type="doi">10.12688/f1000research.22457.1</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000530</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000530</idno><idno type="wicri:Area/Pmc/Curation">000530</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000530</idno><idno type="wicri:Area/Pmc/Checkpoint">000074</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000074</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL
<sup>pro</sup>) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates</title><author><name sortKey="Chen, Yu Wai" sort="Chen, Yu Wai" uniqKey="Chen Y" first="Yu Wai" last="Chen">Yu Wai Chen</name><affiliation wicri:level="1"><nlm:aff id="a1">Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hunghom, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hunghom</wicri:regionArea><wicri:noRegion>Hunghom</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="a2">State Key Laboratory of Chemical Biology and Drug Discovery, Hunghom, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>State Key Laboratory of Chemical Biology and Drug Discovery, Hunghom</wicri:regionArea><wicri:noRegion>Hunghom</wicri:noRegion></affiliation></author><author><name sortKey="Yiu, Chin Pang Bennu" sort="Yiu, Chin Pang Bennu" uniqKey="Yiu C" first="Chin-Pang Bennu" last="Yiu">Chin-Pang Bennu Yiu</name><affiliation wicri:level="1"><nlm:aff id="a3">Independent Researcher, La Costa, Ma On Shan, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>Independent Researcher, La Costa, Ma On Shan</wicri:regionArea><wicri:noRegion>Ma On Shan</wicri:noRegion></affiliation></author><author><name sortKey="Wong, Kwok Yin" sort="Wong, Kwok Yin" uniqKey="Wong K" first="Kwok-Yin" last="Wong">Kwok-Yin Wong</name><affiliation wicri:level="1"><nlm:aff id="a1">Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hunghom, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hunghom</wicri:regionArea><wicri:noRegion>Hunghom</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="a2">State Key Laboratory of Chemical Biology and Drug Discovery, Hunghom, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>State Key Laboratory of Chemical Biology and Drug Discovery, Hunghom</wicri:regionArea><wicri:noRegion>Hunghom</wicri:noRegion></affiliation></author></analytic><series><title level="j">F1000Research</title><idno type="eISSN">2046-1402</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL
<sup>pro</sup>) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart. With the 3CL
<sup>pro</sup> molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache. The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Chan, Jf" uniqKey="Chan J">JF Chan</name></author><author><name sortKey="Yuan, S" uniqKey="Yuan S">S Yuan</name></author><author><name sortKey="Kok, Kh" uniqKey="Kok K">KH Kok</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Muramatsu, T" uniqKey="Muramatsu T">T Muramatsu</name></author><author><name sortKey="Takemoto, C" uniqKey="Takemoto C">C Takemoto</name></author><author><name sortKey="Kim, Yt" uniqKey="Kim Y">YT Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Krivov, Gg" uniqKey="Krivov G">GG Krivov</name></author><author><name sortKey="Shapovalov, Mv" uniqKey="Shapovalov M">MV Shapovalov</name></author><author><name sortKey="Dunbrack, Rl" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">F1000Res</journal-id><journal-id journal-id-type="iso-abbrev">F1000Res</journal-id><journal-id journal-id-type="pmc">F1000Research</journal-id><journal-title-group><journal-title>F1000Research</journal-title></journal-title-group><issn pub-type="epub">2046-1402</issn><publisher><publisher-name>F1000 Research Limited</publisher-name><publisher-loc>London, UK</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32194944</article-id><article-id pub-id-type="pmc">7062204</article-id><article-id pub-id-type="doi">10.12688/f1000research.22457.1</article-id><article-categories><subj-group subj-group-type="heading"><subject>Brief Report</subject></subj-group><subj-group><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL
<sup>pro</sup>) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates</article-title><fn-group content-type="pub-status"><fn><p>[version 1; peer review: 3 approved]</p></fn></fn-group></title-group><contrib-group><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Yu Wai</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Data Curation</role><role content-type="http://credit.casrai.org/">Formal Analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Project Administration</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – Original Draft Preparation</role><role content-type="http://credit.casrai.org/">Writing – Review & Editing</role><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-7833-7533</contrib-id><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>Yiu</surname><given-names>Chin-Pang Bennu</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Formal Analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Project Administration</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – Original Draft Preparation</role><role content-type="http://credit.casrai.org/">Writing – Review & Editing</role><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-3965-3992</contrib-id><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Wong</surname><given-names>Kwok-Yin</given-names></name><role content-type="http://credit.casrai.org/">Funding Acquisition</role><role content-type="http://credit.casrai.org/">Project Administration</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – Review & Editing</role><xref ref-type="corresp" rid="c2">b</xref><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref></contrib><aff id="a1"><label>1</label>Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hunghom, Hong Kong</aff><aff id="a2"><label>2</label>State Key Laboratory of Chemical Biology and Drug Discovery, Hunghom, Hong Kong</aff><aff id="a3"><label>3</label>Independent Researcher, La Costa, Ma On Shan, Hong Kong</aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email xlink:href="mailto:yu-wai.chen@polyu.edu.hk">yu-wai.chen@polyu.edu.hk</email></corresp><corresp id="c2"><label>b</label><email xlink:href="mailto:kwok-yin.wong@polyu.edu.hk">kwok-yin.wong@polyu.edu.hk</email></corresp><fn fn-type="COI-statement"><p>No competing interests were disclosed.</p></fn></author-notes><pub-date pub-type="epub"><day>21</day><month>2</month><year>2020</year></pub-date><pub-date pub-type="collection"><year>2020</year></pub-date><volume>9</volume><elocation-id>129</elocation-id><history><date date-type="accepted"><day>19</day><month>2</month><year>2020</year></date></history><permissions><copyright-statement>Copyright: © 2020 Chen YW et al.</copyright-statement><copyright-year>2020</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="f1000research-9-24784.pdf"></self-uri><abstract><p>We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL
<sup>pro</sup>) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart. With the 3CL
<sup>pro</sup> molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache. The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.</p></abstract><kwd-group kwd-group-type="author"><kwd>COVID-19</kwd><kwd>SARS</kwd><kwd>2019-nCoV</kwd><kwd>3C-like protease</kwd><kwd>drug repurpose</kwd><kwd>antiviral</kwd><kwd>coronavirus</kwd><kwd>virtual screening</kwd><kwd>molecular modelling</kwd><kwd>ledipasvir</kwd><kwd>velpatasvir</kwd><kwd>Hepatitis C virus</kwd><kwd>HCV</kwd></kwd-group><funding-group><award-group id="fund-1" xlink:href="http://dx.doi.org/10.13039/501100004377"><funding-source>Hong Kong Polytechnic University</funding-source><award-id>1-ZVH9</award-id></award-group><award-group id="fund-2" xlink:href="http://dx.doi.org/10.13039/501100007156"><funding-source>Innovation and Technology Commission - Hong Kong</funding-source></award-group><funding-statement>We acknowledge support from the Innovation and Technology Commission of Hong Kong, the Hong Kong Polytechnic University and the Life Science Area of Strategic Fund 1-ZVH9.</funding-statement><funding-statement><italic>The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</italic></funding-statement></funding-group></article-meta></front><sub-article id="report60415" article-type="peer-review"><front-stub><article-id pub-id-type="doi">10.5256/f1000research.24784.r60415</article-id><title-group><article-title>Reviewer response for version 1</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Viprakasit</surname><given-names>Vip</given-names></name><xref ref-type="aff" rid="r60415a1">1</xref><role>Referee</role></contrib><contrib contrib-type="author"><name><surname>Tulalamba</surname><given-names>Warut</given-names></name><xref ref-type="aff" rid="r60415a2">2</xref><role>Co-referee</role></contrib><aff id="r60415a1"><label>1</label>Division of Pediatric Haematology and Oncology, Thalassemia Center, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand</aff><aff id="r60415a2"><label>2</label>Research Division and Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand</aff></contrib-group><author-notes><fn fn-type="COI-statement"><p><bold>Competing interests: </bold>No competing interests were disclosed.</p></fn></author-notes><pub-date pub-type="epub"><day>17</day><month>3</month><year>2020</year></pub-date><permissions><copyright-statement>Copyright: © 2020 Viprakasit V and Tulalamba W</copyright-statement><copyright-year>2020</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><related-article related-article-type="peer-reviewed-article" id="d35e3251" ext-link-type="doi" xlink:href="10.12688/f1000research.22457.1">Version 1</related-article><custom-meta-group><custom-meta><meta-name>recommendation</meta-name><meta-value>approve</meta-value></custom-meta></custom-meta-group></front-stub><body><p>In this article, Chen YW and his colleagues carried out virtual screening using the computational molecular modeling of the viral protein from SARS-CoV-2 or COVID-19 to identify therapeutics targets. The authors presented that 3CLpro protease enzyme of the SARS-CoV-2 is considered to be a promising drug target and repurposing accessible drugs to challenge the globally outbreaking of the SARS-CoV-2. The authors initially used the translated polyprotein (PP1AB) sequence of SARS-CoV-2 and SARS-CoV to prepare for protein structural model. Subsequently, they performed computational virtual screening against this against its using a library of purchasable drugs with the binding site grid. Among > 7,000 repurposing drugs in the screening with their known side effects, the antivirals ledipasir or velpatasvir are potentially used against SARS-CoV-2 infection with minimal side effects. The manuscript is straightforward in both terminology and structure. The manuscript can be considered to be accepted with a minor revision and could be further improved with following points:
<list list-type="order"><list-item><p>Table 2 is mentioned prior Table 1 in the manuscript.</p></list-item><list-item><p>More details of the setting and cut-off used in the virtual screening and analysis should be provided in the Method section.</p></list-item><list-item><p>Table 1 is quite confusing. The importance residues of the SARS-CoV 3CLpro previously reported and the variant residues found in SARS-CoV-2 (this work) should be separated. The amino acid variants of each position should be included. Using the image with the annotation could be an alternative and more informative presentation.</p></list-item><list-item><p>In Table 3, some information should be included in the table, such as molecular weight. In addition, the authors should discuss more about the results shown in the Table 3 to compare the binding energy different between A and B chains.</p></list-item><list-item><p>In the conclusion, the authors proposed velpatasvir and ledipasvir as an attractive candidate. However, based on the virtual screening on the active sites of SARS-CoV-2 3CLpro model, both of them are not ranked as the top list in Chain A screening. Could you please explain this scenario? The results from other virtual screening package (such as Glide or FlexX) should be compared?</p></list-item><list-item><p>To extend the interest of the topic as well as to compare the potential for using repurposing drug in COVID-19 treatment, the drug virtual screening with other viral enzymes might be performed and compared. In this case, since there are several clinical researches for using this drug family (e.g. Lopinavir/ritonavir) in COVID-19 treatment, therefore, the authors can compare the virtual screening model with the clinical outcomes.</p></list-item></list></p><p>We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.</p></body></sub-article><sub-article id="report60414" article-type="peer-review"><front-stub><article-id pub-id-type="doi">10.5256/f1000research.24784.r60414</article-id><title-group><article-title>Reviewer response for version 1</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Ng</surname><given-names>Wai-Lung</given-names></name><xref ref-type="aff" rid="r60414a1">1</xref><role>Referee</role><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-2892-6318</contrib-id></contrib><aff id="r60414a1"><label>1</label>School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong (CUHK), Hong Kong, Hong Kong</aff></contrib-group><author-notes><fn fn-type="COI-statement"><p><bold>Competing interests: </bold>No competing interests were disclosed.</p></fn></author-notes><pub-date pub-type="epub"><day>6</day><month>3</month><year>2020</year></pub-date><permissions><copyright-statement>Copyright: © 2020 Ng WL</copyright-statement><copyright-year>2020</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><related-article related-article-type="peer-reviewed-article" id="d35e3330" ext-link-type="doi" xlink:href="10.12688/f1000research.22457.1">Version 1</related-article><custom-meta-group><custom-meta><meta-name>recommendation</meta-name><meta-value>approve</meta-value></custom-meta></custom-meta-group></front-stub><body><p>Since December 2019, a plethora of cases resembling viral pneumonia has emerged exponentially in Wuhan, China, which is now coined Coronavirus Disease 2019 (COVID-19; formerly known as 2019-nCoV).</p><p> Chen
<italic>et. al.</italic> reported the computational modelling and virtual screening results of the 3C-like protease (3CLpro) of SARS-CoV-2. This study is timely in view of the recent outbreak of COVID-19. The rationale of repurposing existing drugs to tackle the global viral outbreak is sound. The manuscript is also well-written and structured. It should be noted that:
<list list-type="bullet"><list-item><p>The authors compared their model with the recently published crystal structure of 3CLpro and found a high similarity between the two structures. They also obtained a similar list of top-ranked drug candidates when the crystal structure was subjected to the same screening protocol.</p></list-item><list-item><p>Several studies using similar modeling and virtual screening approaches have also been published recently. </p></list-item></list> Some suggestions for improving the manuscript:
<list list-type="bullet"><list-item><p>The authors proposed that the HCV drugs velpatasvir and ledipasvir, and thus Epclusa and Harvoni, could be attractive drug candidates for treating SARS-CoV-2 infection. However, there is no direct evidence to support this claim. To support this claim, the authors should connect the computational results with experimental data. To test their hypothesis, the authors should at least prove (or disprove) that the two HCV drugs could inhibit the biochemical activity of 3CLpro of SARS-CoV-2.</p></list-item><list-item><p>To further test the hypothesis, the two NS5A inhibitors should be tested using in vitro assays such as viral RNA PCR assay.</p></list-item><list-item><p>If there are no such experimental data to support the claim, the authors may consider revising their conclusion to "the computational results provide a rationale for further experimental validation of treating SARS-CoV-2 with velpatasvir and ledipasvir".</p></list-item></list></p><p>I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.</p></body></sub-article><sub-article id="report60688" article-type="peer-review"><front-stub><article-id pub-id-type="doi">10.5256/f1000research.24784.r60688</article-id><title-group><article-title>Reviewer response for version 1</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Jing</given-names></name><xref ref-type="aff" rid="r60688a1">1</xref><role>Referee</role><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-9639-2907</contrib-id></contrib><contrib contrib-type="author"><name><surname>Tan</surname><given-names>Qiaozhu</given-names></name><xref ref-type="aff" rid="r60688a1">1</xref><role>Co-referee</role></contrib><aff id="r60688a1"><label>1</label>School of Life Sciences, Westlake University, Hangzhou, China</aff></contrib-group><author-notes><fn fn-type="COI-statement"><p><bold>Competing interests: </bold>No competing interests were disclosed.</p></fn></author-notes><pub-date pub-type="epub"><day>6</day><month>3</month><year>2020</year></pub-date><permissions><copyright-statement>Copyright: © 2020 Tan Q and Huang J</copyright-statement><copyright-year>2020</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><related-article related-article-type="peer-reviewed-article" id="d35e3425" ext-link-type="doi" xlink:href="10.12688/f1000research.22457.1">Version 1</related-article><custom-meta-group><custom-meta><meta-name>recommendation</meta-name><meta-value>approve</meta-value></custom-meta></custom-meta-group></front-stub><body><p>Yu Wai Chen and co-workers presented a molecular modeling and docking study of the 3CL protease in the SARS-CoV-2 virus. The manuscript started with comparing polyprotein PP1AB sequences of SARS-CoV-2 and SARS-CoV, based on which the 3D structure of SARS-CoV-2 3CLPro protein was constructed. The authors then performed virtual screening against SARS-CoV-2 3CLPro using a library of 7173 purchasable drugs. Considering both binding affinities and known side effects, the authors recommend velpatasvir and ledipasvir, and further suggest combining them with another HCV RdRp inhibitor sofosbuvir, aka repurposing the Epclusa and Harvoni for treating the coronavirus. This is a concise and timely report, and has proposed new therapeutic possibilities for the SARS-CoV-2 virus. The manuscript could be further improved by addressing the following comments.
<list list-type="order"><list-item><p>More details of the docking should be provided. What's the binding energy cutoff used? How is the hits (reported in Table 3) used? 3CLpro is catalytically active as a dimer. How is this considered in the virtual screening? What does the "(B Top scorers)" mean?</p></list-item><list-item><p>In the extended data of virtual screening, one compound could have multiple entries with different ZINC numbers. For example hesperidin corresponds to at least 20 different compounds. What are the difference? And how are different results assembled?</p></list-item><list-item><p>Table 1 is not clear. Please do a column-by-column comparison between different sites of SARS-CoV and SARS-CoV-2. Also please add one-letter amino acid codes for the residues.</p></list-item><list-item><p>The constructed protein structure is very similar to the recently solved crystal structure (6LU7), as "... confirms that the predicted model is good within experimental errors", but the docking results seem to differ significantly. Could the authors explain?</p></list-item></list></p><p>We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.</p></body></sub-article></pmc><affiliations><list><country><li>Hong Kong</li></country></list><tree><country name="Hong Kong"><noRegion><name sortKey="Chen, Yu Wai" sort="Chen, Yu Wai" uniqKey="Chen Y" first="Yu Wai" last="Chen">Yu Wai Chen</name></noRegion><name sortKey="Chen, Yu Wai" sort="Chen, Yu Wai" uniqKey="Chen Y" first="Yu Wai" last="Chen">Yu Wai Chen</name><name sortKey="Wong, Kwok Yin" sort="Wong, Kwok Yin" uniqKey="Wong K" first="Kwok-Yin" last="Wong">Kwok-Yin Wong</name><name sortKey="Wong, Kwok Yin" sort="Wong, Kwok Yin" uniqKey="Wong K" first="Kwok-Yin" last="Wong">Kwok-Yin Wong</name><name sortKey="Yiu, Chin Pang Bennu" sort="Yiu, Chin Pang Bennu" uniqKey="Yiu C" first="Chin-Pang Bennu" last="Yiu">Chin-Pang Bennu Yiu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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