Unrevealing sequence and structural features of novel coronavirus using in silico approaches: The main protease as molecular target
Identifieur interne : 000839 ( Pmc/Corpus ); précédent : 000838; suivant : 000840Unrevealing sequence and structural features of novel coronavirus using in silico approaches: The main protease as molecular target
Auteurs : Joseph Thomas Ortega ; Maria Luisa Serrano ; Flor Helene Pujol ; Hector Rafael RangelSource :
- EXCLI Journal [ 1611-2156 ] ; 2020.
Abstract
Direct-acting antivirals are effective tools to control viral infections. SARS-CoV-2 is a coronavirus associated with the epidemiological outbreak in late 2019. Previous reports showed that HIV-1 protease inhibitors could block SARS-CoV main protease. Based on that and using an
Url:
DOI: 10.17179/excli2020-1189
PubMed: NONE
PubMed Central: 7081067
Links to Exploration step
PMC:7081067Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Unrevealing sequence and structural features of novel coronavirus using <italic>in silico</italic> approaches: The main protease as molecular target</title><author><name sortKey="Ortega, Joseph Thomas" sort="Ortega, Joseph Thomas" uniqKey="Ortega J" first="Joseph Thomas" last="Ortega">Joseph Thomas Ortega</name><affiliation><nlm:aff id="A1">Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA</nlm:aff></affiliation></author><author><name sortKey="Serrano, Maria Luisa" sort="Serrano, Maria Luisa" uniqKey="Serrano M" first="Maria Luisa" last="Serrano">Maria Luisa Serrano</name><affiliation><nlm:aff id="A2">Unidad de Química Medicinal, Facultad de Farmacia, Universidad Central de Venezuela, Caracas, Venezuela</nlm:aff></affiliation></author><author><name sortKey="Pujol, Flor Helene" sort="Pujol, Flor Helene" uniqKey="Pujol F" first="Flor Helene" last="Pujol">Flor Helene Pujol</name><affiliation><nlm:aff id="A3">Laboratorio de Virología Molecular, Centro de Microbiología y Biología Celular, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela</nlm:aff></affiliation></author><author><name sortKey="Rangel, Hector Rafael" sort="Rangel, Hector Rafael" uniqKey="Rangel H" first="Hector Rafael" last="Rangel">Hector Rafael Rangel</name><affiliation><nlm:aff id="A3">Laboratorio de Virología Molecular, Centro de Microbiología y Biología Celular, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmc">7081067</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081067</idno><idno type="RBID">PMC:7081067</idno><idno type="doi">10.17179/excli2020-1189</idno><idno type="pmid">NONE</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000839</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000839</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Unrevealing sequence and structural features of novel coronavirus using <italic>in silico</italic> approaches: The main protease as molecular target</title><author><name sortKey="Ortega, Joseph Thomas" sort="Ortega, Joseph Thomas" uniqKey="Ortega J" first="Joseph Thomas" last="Ortega">Joseph Thomas Ortega</name><affiliation><nlm:aff id="A1">Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA</nlm:aff></affiliation></author><author><name sortKey="Serrano, Maria Luisa" sort="Serrano, Maria Luisa" uniqKey="Serrano M" first="Maria Luisa" last="Serrano">Maria Luisa Serrano</name><affiliation><nlm:aff id="A2">Unidad de Química Medicinal, Facultad de Farmacia, Universidad Central de Venezuela, Caracas, Venezuela</nlm:aff></affiliation></author><author><name sortKey="Pujol, Flor Helene" sort="Pujol, Flor Helene" uniqKey="Pujol F" first="Flor Helene" last="Pujol">Flor Helene Pujol</name><affiliation><nlm:aff id="A3">Laboratorio de Virología Molecular, Centro de Microbiología y Biología Celular, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela</nlm:aff></affiliation></author><author><name sortKey="Rangel, Hector Rafael" sort="Rangel, Hector Rafael" uniqKey="Rangel H" first="Hector Rafael" last="Rangel">Hector Rafael Rangel</name><affiliation><nlm:aff id="A3">Laboratorio de Virología Molecular, Centro de Microbiología y Biología Celular, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela</nlm:aff></affiliation></author></analytic><series><title level="j">EXCLI Journal</title><idno type="eISSN">1611-2156</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>Direct-acting antivirals are effective tools to control viral infections. SARS-CoV-2 is a coronavirus associated with the epidemiological outbreak in late 2019. Previous reports showed that HIV-1 protease inhibitors could block SARS-CoV main protease. Based on that and using an <italic>in silico</italic> approach, we evaluated SARS-CoV-2 main protease as a target for HIV-1 protease inhibitors to reveal the structural features related to their antiviral effect. Our results showed that several HIV inhibitors such as lopinavir, ritonavir, and saquinavir produce strong interaction with the active site of SARS-CoV-2 main protease. Furthermore, broad library protease inhibitors obtained from PubChem and ZINC (<ext-link ext-link-type="uri" xlink:href="www.zinc.docking.org">www.zinc.docking.org</ext-link>) were evaluated. Our analysis revealed 20 compounds that could be clustered into three groups based on their chemical features. Then, these structures could serve as leading compounds to develop a series of derivatives optimizing their activity against SARS-CoV-2 and other coronaviruses. Altogether, the results presented in this work contribute to gain a deep understanding of the molecular pharmacology of SARS-CoV-2 treatment and validate the use of protease inhibitors against SARS-CoV-2.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="De Wilde, Ah" uniqKey="De Wilde A">AH de Wilde</name></author><author><name sortKey="Jochmans, D" uniqKey="Jochmans D">D Jochmans</name></author><author><name sortKey="Posthuma, Cc" uniqKey="Posthuma C">CC Posthuma</name></author><author><name sortKey="Zevenhoven Dobbe, Jc" uniqKey="Zevenhoven Dobbe J">JC Zevenhoven-Dobbe</name></author><author><name sortKey="Van Nieuwkoop, S" uniqKey="Van Nieuwkoop S">S van Nieuwkoop</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Wit, E" uniqKey="De Wit E">E de Wit</name></author><author><name sortKey="Feldmann, F" uniqKey="Feldmann F">F Feldmann</name></author><author><name sortKey="Cronin, J" uniqKey="Cronin J">J Cronin</name></author><author><name sortKey="Jordan, R" uniqKey="Jordan R">R Jordan</name></author><author><name sortKey="Okumura, A" uniqKey="Okumura A">A Okumura</name></author><author><name sortKey="Thomas, T" uniqKey="Thomas T">T Thomas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jenwitheesuk, E" uniqKey="Jenwitheesuk E">E Jenwitheesuk</name></author><author><name sortKey="Samudrala, R" uniqKey="Samudrala R">R Samudrala</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Khalid, M" uniqKey="Khalid M">M Khalid</name></author><author><name sortKey="Al Rabiah, F" uniqKey="Al Rabiah F">F Al Rabiah</name></author><author><name sortKey="Khan, B" uniqKey="Khan B">B Khan</name></author><author><name sortKey="Al Mobeireek, A" uniqKey="Al Mobeireek A">A Al Mobeireek</name></author><author><name sortKey="Butt, Ts" uniqKey="Butt T">TS Butt</name></author><author><name sortKey="Al Mutairy, E" uniqKey="Al Mutairy E">E Al Mutairy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lai, St" uniqKey="Lai S">ST Lai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lim, J" uniqKey="Lim J">J Lim</name></author><author><name sortKey="Jeon, S" uniqKey="Jeon S">S Jeon</name></author><author><name sortKey="Shin, Hy" uniqKey="Shin H">HY Shin</name></author><author><name sortKey="Kim, Mj" uniqKey="Kim M">MJ Kim</name></author><author><name sortKey="Seong, Ym" uniqKey="Seong Y">YM Seong</name></author><author><name sortKey="Lee, Wj" uniqKey="Lee W">WJ Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Menachery, Vd" uniqKey="Menachery V">VD Menachery</name></author><author><name sortKey="Graham, Rl" uniqKey="Graham R">RL Graham</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ortega, Jt" uniqKey="Ortega J">JT Ortega</name></author><author><name sortKey="Serrano, Ml" uniqKey="Serrano M">ML Serrano</name></author><author><name sortKey="Suarez, Ai" uniqKey="Suarez A">AI Suárez</name></author><author><name sortKey="Baptista, J" uniqKey="Baptista J">J Baptista</name></author><author><name sortKey="Pujol, Fh" uniqKey="Pujol F">FH Pujol</name></author><author><name sortKey="Cavallaro, Lv" uniqKey="Cavallaro L">LV Cavallaro</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pedretti, A" uniqKey="Pedretti A">A Pedretti</name></author><author><name sortKey="Villa, L" uniqKey="Villa L">L Villa</name></author><author><name sortKey="Vistoli, G" uniqKey="Vistoli G">G Vistoli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Phillips, Jc" uniqKey="Phillips J">JC Phillips</name></author><author><name sortKey="Braun, R" uniqKey="Braun R">R Braun</name></author><author><name sortKey="Wang, W" uniqKey="Wang W">W Wang</name></author><author><name sortKey="Gumbart, J" uniqKey="Gumbart J">J Gumbart</name></author><author><name sortKey="Tajkhorshid, E" uniqKey="Tajkhorshid E">E Tajkhorshid</name></author><author><name sortKey="Villa, E" uniqKey="Villa E">E Villa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pruijssers, Aj" uniqKey="Pruijssers A">AJ Pruijssers</name></author><author><name sortKey="Denison, Mr" uniqKey="Denison M">MR Denison</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sanchez Linares, I" uniqKey="Sanchez Linares I">I Sánchez-Linares</name></author><author><name sortKey="Perez Sanchez, H" uniqKey="Perez Sanchez H">H Pérez-Sánchez</name></author><author><name sortKey="Cecilia, Jm" uniqKey="Cecilia J">JM Cecilia</name></author><author><name sortKey="Garcia, Jm" uniqKey="Garcia J">JM García</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Savarino, A" uniqKey="Savarino A">A Savarino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sheahan, Tp" uniqKey="Sheahan T">TP Sheahan</name></author><author><name sortKey="Sims, Ac" uniqKey="Sims A">AC Sims</name></author><author><name sortKey="Leist, Sr" uniqKey="Leist S">SR Leist</name></author><author><name sortKey="Sch Fer, A" uniqKey="Sch Fer A">A Schäfer</name></author><author><name sortKey="Won, J" uniqKey="Won J">J Won</name></author><author><name sortKey="Brown, Aj" uniqKey="Brown A">AJ Brown</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sonoiki, E" uniqKey="Sonoiki E">E Sonoiki</name></author><author><name sortKey="Nsanzabana, C" uniqKey="Nsanzabana C">C Nsanzabana</name></author><author><name sortKey="Legac, J" uniqKey="Legac J">J Legac</name></author><author><name sortKey="Sindhe, Km" uniqKey="Sindhe K">KM Sindhe</name></author><author><name sortKey="Derisi, J" uniqKey="Derisi J">J DeRisi</name></author><author><name sortKey="Rosenthal, Pj" uniqKey="Rosenthal P">PJ Rosenthal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Valdivieso, E" uniqKey="Valdivieso E">E Valdivieso</name></author><author><name sortKey="Rangel, A" uniqKey="Rangel A">A Rangel</name></author><author><name sortKey="Moreno, J" uniqKey="Moreno J">J Moreno</name></author><author><name sortKey="Saugar, Jm" uniqKey="Saugar J">JM Saugar</name></author><author><name sortKey="Ca Avate, C" uniqKey="Ca Avate C">C Cañavate</name></author><author><name sortKey="Alvar, J" uniqKey="Alvar J">J Alvar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vanommeslaeghe, K" uniqKey="Vanommeslaeghe K">K Vanommeslaeghe</name></author><author><name sortKey="Hatcher, E" uniqKey="Hatcher E">E Hatcher</name></author><author><name sortKey="Acharya, C" uniqKey="Acharya C">C Acharya</name></author><author><name sortKey="Kundu, S" uniqKey="Kundu S">S Kundu</name></author><author><name sortKey="Zhong, S" uniqKey="Zhong S">S Zhong</name></author><author><name sortKey="Shim, J" uniqKey="Shim J">J Shim</name></author><author><name sortKey="Darian, E" uniqKey="Darian E">E Darian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, M" uniqKey="Wang M">M Wang</name></author><author><name sortKey="Cao, R" uniqKey="Cao R">R Cao</name></author><author><name sortKey="Zhang, L" uniqKey="Zhang L">L Zhang</name></author><author><name sortKey="Yang, X" uniqKey="Yang X">X Yang</name></author><author><name sortKey="Liu, J" uniqKey="Liu J">J Liu</name></author><author><name sortKey="Xu, M" uniqKey="Xu M">M Xu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wong, Mc" uniqKey="Wong M">MC Wong</name></author><author><name sortKey="Javornik Creegen, Sj" uniqKey="Javornik Creegen S">SJ Javornik Creegen</name></author><author><name sortKey="Ajami, Nj" uniqKey="Ajami N">NJ Ajami</name></author><author><name sortKey="Petrosino, Jf" uniqKey="Petrosino J">JF Petrosino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yin, Y" uniqKey="Yin Y">Y Yin</name></author><author><name sortKey="Wunderink, Rg" uniqKey="Wunderink R">RG Wunderink</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zumla, A" uniqKey="Zumla A">A Zumla</name></author><author><name sortKey="Chan, Jf" uniqKey="Chan J">JF Chan</name></author><author><name sortKey="Azhar, Ei" uniqKey="Azhar E">EI Azhar</name></author><author><name sortKey="Hui, Ds" uniqKey="Hui D">DS Hui</name></author><author><name sortKey="Yuen, Ky" uniqKey="Yuen K">KY Yuen</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">EXCLI J</journal-id><journal-id journal-id-type="iso-abbrev">EXCLI J</journal-id><journal-id journal-id-type="publisher-id">EXCLI J</journal-id><journal-title-group><journal-title>EXCLI Journal</journal-title></journal-title-group><issn pub-type="epub">1611-2156</issn><publisher><publisher-name>Leibniz Research Centre for Working Environment and Human Factors</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmc">7081067</article-id><article-id pub-id-type="publisher-id">2020-1189</article-id><article-id pub-id-type="doi">10.17179/excli2020-1189</article-id><article-id pub-id-type="publisher-id">Doc400</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>Unrevealing sequence and structural features of novel coronavirus using <italic>in silico</italic> approaches: The main protease as molecular target</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Ortega</surname><given-names>Joseph Thomas</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Serrano</surname><given-names>Maria Luisa</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Pujol</surname><given-names>Flor Helene</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Rangel</surname><given-names>Hector Rafael</given-names></name><xref ref-type="corresp" rid="COR1">*</xref><xref ref-type="aff" rid="A3">3</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA</aff><aff id="A2"><label>2</label>Unidad de Química Medicinal, Facultad de Farmacia, Universidad Central de Venezuela, Caracas, Venezuela</aff><aff id="A3"><label>3</label>Laboratorio de Virología Molecular, Centro de Microbiología y Biología Celular, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela</aff><author-notes><corresp id="COR1">*To whom correspondence should be addressed: Hector Rafael Rangel, Laboratorio de Virología Molecular, Centro de Microbiología y Biología Celular, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela, E-mail: <email>hrangel2006@gmail.com</email></corresp></author-notes><pub-date pub-type="epub"><day>17</day><month>3</month><year>2020</year></pub-date><pub-date pub-type="collection"><year>2020</year></pub-date><volume>19</volume><fpage>400</fpage><lpage>409</lpage><history><date date-type="received"><day>04</day><month>3</month><year>2020</year></date><date date-type="accepted"><day>16</day><month>3</month><year>2020</year></date></history><permissions><copyright-statement>Copyright © 2020 Ortega et al.</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p><pmc-comment>CREATIVE COMMONS</pmc-comment>This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>) You are free to copy, distribute and transmit the work, provided the original author and source are credited.</license-p></license></permissions><self-uri xlink:type="simple" xlink:href="https://www.excli.de/vol19/Rangel_17032020_proof.pdf">This article is available from https://www.excli.de/vol19/Rangel_17032020_proof.pdf</self-uri><abstract><p>Direct-acting antivirals are effective tools to control viral infections. SARS-CoV-2 is a coronavirus associated with the epidemiological outbreak in late 2019. Previous reports showed that HIV-1 protease inhibitors could block SARS-CoV main protease. Based on that and using an <italic>in silico</italic> approach, we evaluated SARS-CoV-2 main protease as a target for HIV-1 protease inhibitors to reveal the structural features related to their antiviral effect. Our results showed that several HIV inhibitors such as lopinavir, ritonavir, and saquinavir produce strong interaction with the active site of SARS-CoV-2 main protease. Furthermore, broad library protease inhibitors obtained from PubChem and ZINC (<ext-link ext-link-type="uri" xlink:href="www.zinc.docking.org">www.zinc.docking.org</ext-link>) were evaluated. Our analysis revealed 20 compounds that could be clustered into three groups based on their chemical features. Then, these structures could serve as leading compounds to develop a series of derivatives optimizing their activity against SARS-CoV-2 and other coronaviruses. Altogether, the results presented in this work contribute to gain a deep understanding of the molecular pharmacology of SARS-CoV-2 treatment and validate the use of protease inhibitors against SARS-CoV-2.</p></abstract><kwd-group><kwd>Coronavirus</kwd><kwd>SARS-CoV-2</kwd><kwd>protease</kwd><kwd>treatment</kwd><kwd>HIV</kwd></kwd-group></article-meta></front><body><sec sec-type="intro"><title>Introduction</title><p>At present there is not specific treatment for coronavirus infection. However, prior outbreaks have helped to decipher the main pharmacological targets in these viruses. The therapies have been focused on targeting protease, helicase, polymerase, and using immunomodulators such as interferons and corticosteroids (Zumla et al., 2016[<xref rid="R21" ref-type="bibr">21</xref>]). Ribavirin alone or combined with IFN has been the most common therapeutic intervention in patients with SARS and MERS (Khalid et al., 2015[<xref rid="R4" ref-type="bibr">4</xref>]). Also, protease inhibitors have been used <italic>in vitro</italic> and <italic>in vivo</italic> to block coronavirus replication. Lopinavir (LPV) and ritonavir (RTV) are protease inhibitors currently used in HIV therapy that could block SARS-CoV and MERS-CoV main proteases (Savarino 2005[<xref rid="R13" ref-type="bibr">13</xref>]). The combination of lopinavir or ritonavir with ribavirin was associated with improvement in clinical outcome, compared with ribavirin alone, in SARS-CoV-infected patients (Lai, 2005[<xref rid="R5" ref-type="bibr">5</xref>]). During the MERS-CoV outbreak, the Food and Drugs Administration approved the use of ritonavir/lopinavir, based mainly on data obtained from <italic>in vitro</italic> studies (Sheahan et al 2020[<xref rid="R14" ref-type="bibr">14</xref>]). Altogether, these data support the assumption that some protease inhibitors may have an antiviral effect by blocking coronavirus main protease. However, like other RNA viruses, the main challenge associated with antiviral therapy is the selection of resistant variants. Mechanisms of generation of diversity in coronavirus are related to a moderate error rate of the polymerase (with proof-reading capacity) and homologous or heterologous recombination, factors that lead to antigenic drift and shift, similar to those described for Influenza viruses (Menachery et al., 2017[<xref rid="R7" ref-type="bibr">7</xref>]). Thus, viral replication will produce a diverse population of genome variants having different fitness profiles. These variants could be associated with the development of drug resistance (Yin and Wunderink, 2018[<xref rid="R20" ref-type="bibr">20</xref>]; Pruijssers and Denison, 2019[<xref rid="R11" ref-type="bibr">11</xref>]). The ongoing efforts toward discovering efficient drugs to prevent and treat SARS-CoV-2 infection should include the prior structural and pharmacological knowledge gained with the other coronavirus outbreaks. Based on that, in this work was established a comparative theoretical study to rationalize the potential use of protease inhibitors as a treatment against SARS-CoV-2 infections.</p></sec><sec sec-type="materials|methods"><title>Materials and Methods</title><sec><title>Sequence analysis</title><p>Protein sequences of the main protease were individually retrieved from GenBank (accession numbers are shown in the phylogenetic tree, Figure 1<xref ref-type="fig" rid="F1">(Fig. 1)</xref>) for SARS-CoV, SARS-CoV-2 and several Bat-CoV from the genus Betacoronavirus.</p></sec><sec><title>Molecular docking</title><p>The coordinates for SARS-CoV and SARS-CoV-2 main proteases were obtained from the protein data bank, PDB code 1UJ1/2GX4 and 6LU7 respectively. Also, HIV-1 protease bounded to lopinavir under PDB code 1MIU and Bat HKU4 coronavirus PDB code 2YNB were evaluated. The PDB files to be used under further computational analysis were optimized by removing co-crystallized molecules and all crystallographic water molecules. Hydrogens were added and partial charges were assigned to all atoms. The obtained PDB files for each protein were further submitted to restrained molecular mechanics refinement. All molecular dynamics simulations described in this study were performed with NAMD 2.12 (Phillips et al., 2005[<xref rid="R10" ref-type="bibr">10</xref>]), Vega ZZ 3.1.0.21 (Pedretti et al., 2004[<xref rid="R9" ref-type="bibr">9</xref>]; Vanommeslaeghe et al., 2010[<xref rid="R17" ref-type="bibr">17</xref>]) as described in Ortega et al. (2019[<xref rid="R8" ref-type="bibr">8</xref>]). Following, structural analysis of the binding pocket was developed by using CASTp 3.0 software using the http://sts.bioe.uic.edu/castp/ server. The ligand-binding pocket located in the catalytic site was obtained manually and then verified by a priori docking approach with lopinavir by using the Achilles Blind Docking server (Sánchez-Linares et al., 2012[<xref rid="R12" ref-type="bibr">12</xref>]). The 3D structure of each inhibitor was obtained from PubChem. Also, public libraries for protease inhibitors were obtained from PubChem and ZINC databases. Molecular docking was performed with VINA/VegaZZ 3.1.0.21 and 30 runs conducted for each compound. The results were prioritized according to the predicted binding energy in kcal/mol. The results obtained from the docking simulation were visualized with the Biovia Discovery Studio Visualizer 17.2.0 software.</p></sec><sec><title>ADME compound characterization</title><p>A comprehensive analysis of physicochemical descriptors, as well as ADME parameters, pharmacokinetic properties, drug-like nature, and medicinal chemistry for the top 5 compounds obtained from the library virtually screened, was carried out by using SWISSADME tools. These tools were asset through the website at <ext-link ext-link-type="uri" xlink:href="http://www.swissadme.ch">http://www.swissadme.ch</ext-link>. </p></sec></sec><sec sec-type="results"><title>Results</title><sec><title>Homology sequence analysis of the main protease of SARS-CoVs and related Bat-CoVs</title><p>Phylogenetic analysis of the main protease protein sequences of SARS-CoVs and Bat-CoVs is shown in Figure 1<xref ref-type="fig" rid="F1">(Fig. 1)</xref>. The results are in agreement with recent reports of an independent introduction of SARS-CoV-2 from a Bat-CoV, different from the spillover which led to the introduction of SARS-CoV, being the Bat-CoV of <italic>Rhinolophus affinis</italic> the probable ancestor of this new virus (Wong et al., 2020[<xref rid="R19" ref-type="bibr">19</xref>]). The sequences of the whole main protease of this Bat-CoV and of SARS-CoV-2 share 99.3 % identity, while the MERS-CoV protease was only 50.6% identical (Figure 1<xref ref-type="fig" rid="F1">(Fig. 1)</xref>). The main protease sequence is highly conserved among all the SARS-like coronaviruses from human and related CoVs from other animals (Figure 1<xref ref-type="fig" rid="F1">(Fig. 1)</xref>).</p></sec><sec><title>Structural analysis of the main protease</title><p>The SARS-CoV and SARS-CoV-2 proteins exhibit 96 % sequence identity to each other (Figure 1<xref ref-type="fig" rid="F1">(Fig. 1)</xref>). Figure 2<xref ref-type="fig" rid="F2">(Fig. 2)</xref> shows the 3D representation for Bat-CoV, SARS-CoV, and SARS-CoV-2 main proteases and indeed, very similar structures were observed, particularly when comparing SARS-CoV proteases, although very different to the one of HIV-1. Interestingly the SARS-CoV-2 protease shares 21/29 amino acids involved in the drug interaction with SARS-CoV protease, while this later exhibits only 21 amino acids involved in this interaction (Figure 3<xref ref-type="fig" rid="F3">(Fig. 3)</xref>). SARS-CoV-2 protease has an active site with a surface accessible to solvent of 356Å and SARS-CoV only 256 Å (Figure 3<xref ref-type="fig" rid="F3">(Fig. 3)</xref>).</p><p>I<italic>n silico </italic>data demonstrated that the different protease inhibitors, used against HIV-1, could interact with the active site of SARS-CoV-2 protease producing an interaction with a binding energy lower than -6.9 Kcal/mol. However, the compound that produced the strongest interaction with the active site was saquinavir, with a binding energy of -9.6 Kcal/mol (Table 1<xref ref-type="fig" rid="T1">(Tab. 1)</xref>). Binding energy of SARS-CoV-2 main protease to Saquinavir (SQV) and LPV were slightly higher, but similar, to the one of HIV-1 protease (Table 1<xref ref-type="fig" rid="T1">(Tab. 1)</xref>). The interaction of LPV, SQV and RTV with the SARS-CoV-2 main protease is shown in Figure 4<xref ref-type="fig" rid="F4">(Fig. 4)</xref>, the different amino-acids involved in the interaction with all these drugs are also shown.</p><p>In order to contribute with further studies related to developing more effective drugs, in this work was evaluated a broad library of protease inhibitors available in the ZINC database (over 100 compounds) and PubChem (over 200 compounds). After molecular docking, compounds were prioritized based on binding energies. The top 20 compounds were clustered using a hierarchical matrix and represented into a heat map (Figure 5<xref ref-type="fig" rid="F5">(Fig. 5)</xref>). These compounds could be clustered into three big groups based on their chemical structures. Also, the binding energies and chemical motives for each compound are shown in Table 2<xref ref-type="fig" rid="T2">(Tab. 2)</xref>. Interestingly, in the output of this virtual screening at least 5 compounds, representatives of these chemical clusters with binding energy around -8.2 Kcal/mol, were obtained. These scaffolds could be used as leading compounds to further chemical optimization to develop more potent inhibitors. The structure and main ADME parameters for each inhibitor are shown in Figure 6<xref ref-type="fig" rid="F6">(Fig. 6)</xref>, in general the 5 compounds shown, have physicochemical parameters under the expected values for a good drug.</p></sec></sec><sec sec-type="discussion"><title>Discussion</title><p>Due to the rapid spread of SARS-CoV-2, affecting more than 70 countries, therapeutic alternatives are urgently required. Viral main protease plays a pivotal role in coronavirus replication. This enzyme is responsible for the cleavage of the polyprotein, producing functional proteins that will be packed into the virion. The molecular study of SARS-CoV-2 protease showed that this virus has high homology with SARS-CoV protease. Previous data suggest the use of protease inhibitors as potential inhibitors of SARS-CoV protease, in special some of those used for HIV-1 therapy. HIV-1 protease is an aspartyl protease, while in coronavirus it is a cysteine protease. However, the inhibition by protease inhibitors could be driven by a similar mechanism. HIV-1 is one of the best-studied models in antiviral research, their targets are well characterized and its inhibition by drugs has been broadly studied. Protease inhibitors play a main role in HIV-1 therapy. Furthermore, these compounds have shown inhibitory effects over proteases from pathogens such as Leishmania and malaria (Valdivieso et al., 2010[<xref rid="R16" ref-type="bibr">16</xref>]; Sonoiki et al., 2016[<xref rid="R15" ref-type="bibr">15</xref>]; de Wilde et al., 2014[<xref rid="R1" ref-type="bibr">1</xref>]). Thus, the use of protease inhibitors in other viral species could be supported by these non-specific protease inhibitions. Previous reports showed the inhibition of SARS-CoV protease by protease inhibitors used in HIV-1 therapy, being an interesting pharmacological target to treat SARS-CoV-2. Previously, scientific reports showed that some HIV-1 protease inhibitors could decrease SARS-CoV replication (Savarino, 2005[<xref rid="R13" ref-type="bibr">13</xref>]). Nevertheless, not all of the protease inhibitors showed the same efficacy against this virus (Jenwitheesuk and Samudrala, 2003[<xref rid="R3" ref-type="bibr">3</xref>]). Based on that, in this work, we established an <italic>in silico</italic> approach to validate the inhibition of SARS-CoV-2 protease by HIV-1 protease inhibitor. The results showed that the main protease inhibitors used in HIV-1 therapy could produce a decrease in the protease activity in coronavirus enzyme. The compound with the highest binding affinity was saquinavir. Preliminary reports are showing that patients infected with SARS-CoV-2 and treated with lopinavir could achieve viral clearance (Lim et al., 2020[<xref rid="R6" ref-type="bibr">6</xref>]). Our study suggests that drugs such as SQV and LPV have shown slightly higher, but comparative binding energies against the SARS-CoV-2, than HIV-1 protease. Thus, based on their safety profiles, SQV and LPV could be used as therapy and/or pre-exposure prophylaxis to reduce new infections by SARS-CoV-2. Additionally, the data obtained from prior outbreaks, the clinical results obtained by using protease inhibitors in patients infected with SARS-CoV-2, and the results shown here, support the use of protease inhibitors to treat SARS-CoV-2. </p><p>In addition, to contribute to further development of antiviral drugs against SARS-CoV-2, in this work experimental compounds against the SARS-CoV-2 protease were evaluated by virtual screening. Some compounds showed comparable binding energy values to the SARS-CoV-2 protease than to those observed for SQV, LPV and RTV. ADME (for Absorption, Distribution, Metabolism, and Excretion) parameters estimation for new drugs, significantly helps to reduce the pharmacokinetics-related failure in clinical phases. These results evidence that these compounds could be suitable for further medicinal chemistry optimization to produce the second generation of inhibitors more specific and potent against SARS-CoV-2.</p><p>Other antivirals have been evaluated in SARS-CoV-2 as the polymerase inhibitor remdesivir, a nucleotide analog (currently in clinical trials against Ebola virus and SARS-CoV-2), alone or in combination with chloroquine, an inhibitor of lysosome acidification, with interesting results (Wang et al., 2020[<xref rid="R18" ref-type="bibr">18</xref>]; de Wit et al., 2020[<xref rid="R2" ref-type="bibr">2</xref>]). Therefore, proposing a combinatory therapy against SARS-CoV-2 could be a feasible approach. The starting therapeutic scheme could include remdesivir, with the disadvantage of its intravenous administration, and HIV-1 protease inhibitors such as Lopinavir or Saquinavir. Nevertheless, more pre-clinical and clinical data are required to support the development of new therapies against SARS-CoV-2.</p></sec></body><back><ref-list><ref id="R1"><label>1</label><element-citation publication-type="journal"><person-group><name><surname>de Wilde</surname><given-names>AH</given-names></name><name><surname>Jochmans</surname><given-names>D</given-names></name><name><surname>Posthuma</surname><given-names>CC</given-names></name><name><surname>Zevenhoven-Dobbe</surname><given-names>JC</given-names></name><name><surname>van Nieuwkoop</surname><given-names>S</given-names></name><name><surname>Bestebroer</surname><given-names>TM</given-names></name><etal></etal></person-group><article-title>Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture</article-title><source>Antimicrob Agents Chemother</source><year>2014</year><volume>58</volume><fpage>4875–84</fpage><pub-id pub-id-type="pmid">24841269</pub-id></element-citation></ref><ref id="R2"><label>2</label><element-citation publication-type="journal"><person-group><name><surname>de Wit</surname><given-names>E</given-names></name><name><surname>Feldmann</surname><given-names>F</given-names></name><name><surname>Cronin</surname><given-names>J</given-names></name><name><surname>Jordan</surname><given-names>R</given-names></name><name><surname>Okumura</surname><given-names>A</given-names></name><name><surname>Thomas</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection</article-title><source>Proc Natl Acad Sci U S A</source><year>2020</year><volume>13</volume><fpage>epub ahead of print</fpage></element-citation></ref><ref id="R3"><label>3</label><element-citation publication-type="journal"><person-group><name><surname>Jenwitheesuk</surname><given-names>E</given-names></name><name><surname>Samudrala</surname><given-names>R</given-names></name></person-group><article-title>Identifying inhibitors of the SARS coronavirus proteinase</article-title><source>Bioorg Med Chem Lett</source><year>2003</year><volume>13</volume><fpage>3989</fpage><lpage>3992</lpage><pub-id pub-id-type="pmid">14592491</pub-id></element-citation></ref><ref id="R4"><label>4</label><element-citation publication-type="journal"><person-group><name><surname>Khalid</surname><given-names>M</given-names></name><name><surname>Al Rabiah</surname><given-names>F</given-names></name><name><surname>Khan</surname><given-names>B</given-names></name><name><surname>Al Mobeireek</surname><given-names>A</given-names></name><name><surname>Butt</surname><given-names>TS</given-names></name><name><surname>Al Mutairy</surname><given-names>E</given-names></name></person-group><article-title>Ribavirin and interferon-α2b as primary and preventive treatment for Middle East respiratory syndrome coronavirus: a preliminary report of two cases</article-title><source>Antivir Ther</source><year>2015</year><volume>20</volume><fpage>87–91</fpage><pub-id pub-id-type="pmid">24831606</pub-id></element-citation></ref><ref id="R5"><label>5</label><element-citation publication-type="journal"><person-group><name><surname>Lai</surname><given-names>ST</given-names></name></person-group><article-title>Treatment of severe acute respiratory syndrome</article-title><source>Eur J Clin Microbiol Infect Dis</source><year>2005</year><volume>24</volume><fpage>583–91</fpage><pub-id pub-id-type="pmid">16172857</pub-id></element-citation></ref><ref id="R6"><label>6</label><element-citation publication-type="journal"><person-group><name><surname>Lim</surname><given-names>J</given-names></name><name><surname>Jeon</surname><given-names>S</given-names></name><name><surname>Shin</surname><given-names>HY</given-names></name><name><surname>Kim</surname><given-names>MJ</given-names></name><name><surname>Seong</surname><given-names>YM</given-names></name><name><surname>Lee</surname><given-names>WJ</given-names></name><etal></etal></person-group><article-title>Case of the index patient who caused tertiary transmission of COVID-19 infection in Korea: the application of Lopinavir/Ritonavir for the treatment of COVID-19 infected pneumonia monitored by quantitative RT-PCR</article-title><source>J Korean Med Sci</source><year>2020</year><volume>35</volume><issue>6</issue><fpage>e79</fpage><pub-id pub-id-type="pmid">32056407</pub-id></element-citation></ref><ref id="R7"><label>7</label><element-citation publication-type="journal"><person-group><name><surname>Menachery</surname><given-names>VD</given-names></name><name><surname>Graham</surname><given-names>RL</given-names></name><name><surname>Baric</surname><given-names>RS</given-names></name></person-group><article-title>Jumping species-a mechanism for coronavirus persistence and survival</article-title><source>Curr Opin Virol</source><year>2017</year><volume>23</volume><fpage>1</fpage><lpage>7</lpage><pub-id pub-id-type="pmid">28214731</pub-id></element-citation></ref><ref id="R8"><label>8</label><element-citation publication-type="journal"><person-group><name><surname>Ortega</surname><given-names>JT</given-names></name><name><surname>Serrano</surname><given-names>ML</given-names></name><name><surname>Suárez</surname><given-names>AI</given-names></name><name><surname>Baptista</surname><given-names>J</given-names></name><name><surname>Pujol</surname><given-names>FH</given-names></name><name><surname>Cavallaro</surname><given-names>LV</given-names></name><etal></etal></person-group><article-title>Antiviral activity of flavonoids present in aerial parts of Marcetia taxifolia against Hepatitis B virus, Poliovirus, and Herpes Simplex Virus in vitro</article-title><source>EXCLI J</source><year>2019</year><volume>18</volume><fpage>1037</fpage><lpage>1048</lpage><pub-id pub-id-type="pmid">31762727</pub-id></element-citation></ref><ref id="R9"><label>9</label><element-citation publication-type="journal"><person-group><name><surname>Pedretti</surname><given-names>A</given-names></name><name><surname>Villa</surname><given-names>L</given-names></name><name><surname>Vistoli</surname><given-names>G</given-names></name></person-group><article-title>VEGA - An open platform to develop chemo-bio-informatics applications, using plug-in architecture and script programming</article-title><source>J Comput Aided Mol Des</source><year>2004</year><volume>18</volume><fpage>167–73</fpage><pub-id pub-id-type="pmid">15368917</pub-id></element-citation></ref><ref id="R10"><label>10</label><element-citation publication-type="journal"><person-group><name><surname>Phillips</surname><given-names>JC</given-names></name><name><surname>Braun</surname><given-names>R</given-names></name><name><surname>Wang</surname><given-names>W</given-names></name><name><surname>Gumbart</surname><given-names>J</given-names></name><name><surname>Tajkhorshid</surname><given-names>E</given-names></name><name><surname>Villa</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Scalable molecular dynamics with NAMD</article-title><source>J Comput Chem</source><year>2005</year><volume>26</volume><fpage>1781–1802</fpage><pub-id pub-id-type="pmid">16222654</pub-id></element-citation></ref><ref id="R11"><label>11</label><element-citation publication-type="journal"><person-group><name><surname>Pruijssers</surname><given-names>AJ</given-names></name><name><surname>Denison</surname><given-names>MR</given-names></name></person-group><article-title>Nucleoside analogues for the treatment of coronavirus infections</article-title><source>Curr Opin Virol</source><year>2019</year><volume>35</volume><fpage>57</fpage><lpage>62</lpage><pub-id pub-id-type="pmid">31125806</pub-id></element-citation></ref><ref id="R12"><label>12</label><element-citation publication-type="journal"><person-group><name><surname>Sánchez-Linares</surname><given-names>I</given-names></name><name><surname>Pérez-Sánchez</surname><given-names>H</given-names></name><name><surname>Cecilia</surname><given-names>JM</given-names></name><name><surname>García</surname><given-names>JM</given-names></name></person-group><article-title>High-throughput parallel blind virtual screening using BINDSURF</article-title><source>BMC Bioinformatics</source><year>2012</year><volume>13</volume><issue>Suppl 14</issue><fpage>S13</fpage></element-citation></ref><ref id="R13"><label>13</label><element-citation publication-type="journal"><person-group><name><surname>Savarino</surname><given-names>A</given-names></name></person-group><article-title>Expanding the frontiers of existing antiviral drugs: possible effects of HIV-1 protease inhibitors against SARS and avian influenza</article-title><source>J Clin Virol</source><year>2005</year><volume>34</volume><fpage>170</fpage><lpage>178</lpage><pub-id pub-id-type="pmid">15893956</pub-id></element-citation></ref><ref id="R14"><label>14</label><element-citation publication-type="journal"><person-group><name><surname>Sheahan</surname><given-names>TP</given-names></name><name><surname>Sims</surname><given-names>AC</given-names></name><name><surname>Leist</surname><given-names>SR</given-names></name><name><surname>Schäfer</surname><given-names>A</given-names></name><name><surname>Won</surname><given-names>J</given-names></name><name><surname>Brown</surname><given-names>AJ</given-names></name><etal></etal></person-group><article-title>Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV</article-title><source>Nat Commun</source><year>2020</year><volume>11</volume><issue>1</issue><fpage>222</fpage><pub-id pub-id-type="pmid">31924756</pub-id></element-citation></ref><ref id="R15"><label>15</label><element-citation publication-type="journal"><person-group><name><surname>Sonoiki</surname><given-names>E</given-names></name><name><surname>Nsanzabana</surname><given-names>C</given-names></name><name><surname>Legac</surname><given-names>J</given-names></name><name><surname>Sindhe</surname><given-names>KM</given-names></name><name><surname>DeRisi</surname><given-names>J</given-names></name><name><surname>Rosenthal</surname><given-names>PJ</given-names></name></person-group><article-title>Altered Plasmodium falciparum sensitivity to the antiretroviral protease inhibitor lopinavir associated with polymorphisms in pfmdr1</article-title><source>Antimicrob Agents Chemother</source><year>2017</year><volume>61</volume><issue>1</issue><fpage>01949</fpage><lpage>01916</lpage></element-citation></ref><ref id="R16"><label>16</label><element-citation publication-type="journal"><person-group><name><surname>Valdivieso</surname><given-names>E</given-names></name><name><surname>Rangel</surname><given-names>A</given-names></name><name><surname>Moreno</surname><given-names>J</given-names></name><name><surname>Saugar</surname><given-names>JM</given-names></name><name><surname>Cañavate</surname><given-names>C</given-names></name><name><surname>Alvar</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Effects of HIV aspartyl-proteinase inhibitors on Leishmania sp</article-title><source>Exp Parasitol</source><year>2010</year><volume>126</volume><fpage>557</fpage><lpage>563</lpage><pub-id pub-id-type="pmid">20566367</pub-id></element-citation></ref><ref id="R17"><label>17</label><element-citation publication-type="journal"><person-group><name><surname>Vanommeslaeghe</surname><given-names>K</given-names></name><name><surname>Hatcher</surname><given-names>E</given-names></name><name><surname>Acharya</surname><given-names>C</given-names></name><name><surname>Kundu</surname><given-names>S</given-names></name><name><surname>Zhong</surname><given-names>S</given-names></name><name><surname>Shim</surname><given-names>J</given-names></name><name><surname>Darian</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields</article-title><source>J Comput Chem</source><year>2010</year><volume>1</volume><fpage>671</fpage><lpage>690</lpage></element-citation></ref><ref id="R18"><label>18</label><element-citation publication-type="journal"><person-group><name><surname>Wang</surname><given-names>M</given-names></name><name><surname>Cao</surname><given-names>R</given-names></name><name><surname>Zhang</surname><given-names>L</given-names></name><name><surname>Yang</surname><given-names>X</given-names></name><name><surname>Liu</surname><given-names>J</given-names></name><name><surname>Xu</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro</article-title><source>Cell Res</source><year>2020</year><volume>30</volume><fpage>269–271</fpage><pub-id pub-id-type="pmid">32020029</pub-id></element-citation></ref><ref id="R19"><label>19</label><element-citation publication-type="journal"><person-group><name><surname>Wong</surname><given-names>MC</given-names></name><name><surname>Javornik Creegen</surname><given-names>SJ</given-names></name><name><surname>Ajami</surname><given-names>NJ</given-names></name><name><surname>Petrosino</surname><given-names>JF</given-names></name></person-group><article-title>Evidence of recombination in coronaviruses implicating pangolin origins of nCoV-2019</article-title><source>bioRxiv</source><year>2020</year><comment>Available from: </comment><pub-id pub-id-type="doi">10.1101/2020.02.07.939207</pub-id></element-citation></ref><ref id="R20"><label>20</label><element-citation publication-type="journal"><person-group><name><surname>Yin</surname><given-names>Y</given-names></name><name><surname>Wunderink</surname><given-names>RG</given-names></name></person-group><article-title>MERS, SARS and other coronaviruses as causes of pneumonia</article-title><source>Respirology</source><year>2018</year><volume>23</volume><fpage>130</fpage><lpage>137</lpage><pub-id pub-id-type="pmid">29052924</pub-id></element-citation></ref><ref id="R21"><label>21</label><element-citation publication-type="journal"><person-group><name><surname>Zumla</surname><given-names>A</given-names></name><name><surname>Chan</surname><given-names>JF</given-names></name><name><surname>Azhar</surname><given-names>EI</given-names></name><name><surname>Hui</surname><given-names>DS</given-names></name><name><surname>Yuen</surname><given-names>KY</given-names></name></person-group><article-title>Coronaviruses - drug discovery and therapeutic options</article-title><source>Nat Rev Drug Discov</source><year>2016</year><volume>15</volume><fpage>327</fpage><lpage>347</lpage><pub-id pub-id-type="pmid">26868298</pub-id></element-citation></ref></ref-list></back><floats-group><fig id="T1" position="float"><label>Table 1</label><caption><title>Molecular docking of Protease inhibitors used against HIV-1 over SARS-CoVs main proteases</title></caption><graphic xlink:href="EXCLI-19-400-t-001"></graphic></fig><fig id="T2" position="float"><label>Table 2</label><caption><title>Binding energy (BE) values of the best 20 compounds selected as potential inhibitors of SARS-CoV-2 protease. Compound structures were obtained from ZINC database (Bold) and PubChem (italics), lowest BE compound of each group are shown in red.</title></caption><graphic xlink:href="EXCLI-19-400-t-002"></graphic></fig><fig id="F1" position="float"><label>Figure 1</label><caption><title>Phylogenetic analysis of SARS-CoV-2 and other coronaviruses main protease protein. Phylogenetic tree constructed with Poisson correction and 100 bootstrap replicas. The sequences are named with their accession number. The percent homology with SARS-CoV-2 protease protein is shown for some proteins.</title></caption><graphic xlink:href="EXCLI-19-400-g-001"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><title>Coronavirus main proteases. Graphical representation for each protease was achieved in Biovia Discovery Studio Visualizer by using the coordinates obtained from the Protein Data Bank. Structure for A) Bat-CoV (2YNB), B) SARS-CoV (2GX4), C) SARS-CoV-2 (6LU7) are shown. Also, a comparison by molecular overlapping between these structures is shown in D. The main residues and changes in SARS-CoV-2 compared to SARS-CoV are shown in E. The HIV-1 protease (1MIU) is shown in F.</title></caption><graphic xlink:href="EXCLI-19-400-g-002"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><title>Coronavirus main proteases. Topological analysis of the catalytic site for SARS-CoV (A) and SARS-CoV-2 (B) main proteases. Conformational residues are highlighted in blue.</title></caption><graphic xlink:href="EXCLI-19-400-g-003"></graphic></fig><fig id="F4" position="float"><label>Figure 4</label><caption><title>Molecular docking of HIV protease inhibitors on SARS-CoV-2 main protease. The molecular docking output represented as lower binding energy frame is shown for each inhibitor. 3D (left) and 2D (right) representations showing the main interaction between the inhibitor and the receptor are displayed. A) Saquinavir, B) Ritonavir, and C) Lopinavir</title></caption><graphic xlink:href="EXCLI-19-400-g-004"></graphic></fig><fig id="F5" position="float"><label>Figure 5</label><caption><title>Hierarchical clustering of the top 20 best protease inhibitors obtained from public libraries (ZINC and PubChem) that could block SARS-CoV-2 protease. The compounds were clustered by chemical structure based in the Tanimoto coefficient where 0: the same structure and 1: no chemical relationship.</title></caption><graphic xlink:href="EXCLI-19-400-g-005"></graphic></fig><fig id="F6" position="float"><label>Figure 6</label><caption><title>Chemical structure and ADME parameters of top five protease inhibitors obtained from public libraries (ZINC and PubChem) that could block SARS-CoV-2 protease. The colored zone is the suitable physicochemical space for oral bioavailability. LIPO (Lipophility): -0.7 </title> </caption><graphic xlink:href="EXCLI-19-400-g-006"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/CovidV2/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000839 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000839 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= CovidV2
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:7081067
|texte= Unrevealing sequence and structural features of novel coronavirus using in silico approaches: The main protease as molecular target
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:NONE" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a CovidV2
| This area was generated with Dilib version V0.6.33. |  |