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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Molecular docking, molecular dynamics simulations and reactivity, studies on
approved drugs library targeting ACE2 and SARS-CoV-2 binding with ACE2</title><author><name sortKey="Khelfaoui, Hadjer" sort="Khelfaoui, Hadjer" uniqKey="Khelfaoui H" first="Hadjer" last="Khelfaoui">Hadjer Khelfaoui</name><affiliation><nlm:aff id="AF0001"><institution>Group of Computational Pharmaceutical Chemistry, LMCE Laboratory, Faculty of Exact and Natural Sciences, Department of Matter Sciences, University of Biskra</institution>,<city>Biskra</city>,<country>Algeria</country></nlm:aff></affiliation></author><author><name sortKey="Harkati, Dalal" sort="Harkati, Dalal" uniqKey="Harkati D" first="Dalal" last="Harkati">Dalal Harkati</name><affiliation><nlm:aff id="AF0001"><institution>Group of Computational Pharmaceutical Chemistry, LMCE Laboratory, Faculty of Exact and Natural Sciences, Department of Matter Sciences, University of Biskra</institution>,<city>Biskra</city>,<country>Algeria</country></nlm:aff></affiliation></author><author><name sortKey="Saleh, Basil A" sort="Saleh, Basil A" uniqKey="Saleh B" first="Basil A." last="Saleh">Basil A. Saleh</name><affiliation><nlm:aff id="AF0002"><institution>Department of Chemistry, College of Science, University of Basrah</institution>,<city>Basrah</city>,<country>Iraq</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32752951</idno><idno type="pmc">7484571</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484571</idno><idno type="RBID">PMC:7484571</idno><idno type="doi">10.1080/07391102.2020.1803967</idno><date when="????">????</date><idno type="wicri:Area/Pmc/Corpus">000210</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000210</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Molecular docking, molecular dynamics simulations and reactivity, studies on
approved drugs library targeting ACE2 and SARS-CoV-2 binding with ACE2</title><author><name sortKey="Khelfaoui, Hadjer" sort="Khelfaoui, Hadjer" uniqKey="Khelfaoui H" first="Hadjer" last="Khelfaoui">Hadjer Khelfaoui</name><affiliation><nlm:aff id="AF0001"><institution>Group of Computational Pharmaceutical Chemistry, LMCE Laboratory, Faculty of Exact and Natural Sciences, Department of Matter Sciences, University of Biskra</institution>,<city>Biskra</city>,<country>Algeria</country></nlm:aff></affiliation></author><author><name sortKey="Harkati, Dalal" sort="Harkati, Dalal" uniqKey="Harkati D" first="Dalal" last="Harkati">Dalal Harkati</name><affiliation><nlm:aff id="AF0001"><institution>Group of Computational Pharmaceutical Chemistry, LMCE Laboratory, Faculty of Exact and Natural Sciences, Department of Matter Sciences, University of Biskra</institution>,<city>Biskra</city>,<country>Algeria</country></nlm:aff></affiliation></author><author><name sortKey="Saleh, Basil A" sort="Saleh, Basil A" uniqKey="Saleh B" first="Basil A." last="Saleh">Basil A. Saleh</name><affiliation><nlm:aff id="AF0002"><institution>Department of Chemistry, College of Science, University of Basrah</institution>,<city>Basrah</city>,<country>Iraq</country></nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Biomolecular Structure & Dynamics</title><idno type="ISSN">0739-1102</idno><idno type="eISSN">1538-0254</idno><imprint><date when="????">????</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Abstract</title><p>The recent new contagion coronavirus 2019 (COVID-19) disease is a new generation of
severe acute respiratory syndrome coronavirus-2 SARS-CoV-2 which infected millions
confirmed cases and hundreds of thousands death cases around the world so far. Molecular
docking combined with molecular dynamics is one of the most important tools of drug
discovery and drug design, which it used to examine the type of binding between the ligand
and its protein enzyme. Global reactivity has important properties, which enable chemists
to understand the chemical reactivity and kinetic stability of compounds. In this study,
molecular docking and reactivity were applied for eighteen drugs, which are similar in
structure to chloroquine and hydroxychloroquine, the potential inhibitors to
angiotensin-converting enzyme (ACE2). Those drugs were selected from DrugBank. The
reactivity, molecular docking and molecular dynamics were performed for two receptors ACE2
and [SARS-CoV-2/ACE2] complex receptor in two active sites to find a ligand, which may
inhibit COVID-19. The results obtained from this study showed that <bold>Ramipril</bold>,
<bold>Delapril</bold> and <bold>Lisinopril</bold> could bind with ACE2 receptor and
[SARS-CoV-2/ACE2] complex better than chloroquine and hydroxychloroquine. This new
understanding should help to improve predictions of the impact of such alternatives on
COVID-19.</p><p>Communicated by Ramaswamy H. Sarma</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></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">J Biomol Struct Dyn</journal-id><journal-id journal-id-type="iso-abbrev">J Biomol Struct Dyn</journal-id><journal-title-group><journal-title>Journal of Biomolecular Structure & Dynamics</journal-title></journal-title-group><issn pub-type="ppub">0739-1102</issn><issn pub-type="epub">1538-0254</issn><publisher><publisher-name>Taylor & Francis</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32752951</article-id><article-id pub-id-type="pmc">7484571</article-id><article-id pub-id-type="doi">10.1080/07391102.2020.1803967</article-id><article-id pub-id-type="publisher-id">1803967</article-id><article-version vocab="JAV" vocab-identifier="http://www.niso.org/publications/rp/RP-8-2008.pdf" vocab-term="Version of Record" article-version-type="VoR">Version of
Record</article-version><article-categories><subj-group subj-group-type="article-type"><subject>Research Article</subject></subj-group><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Molecular docking, molecular dynamics simulations and reactivity, studies on
approved drugs library targeting ACE2 and SARS-CoV-2 binding with ACE2</article-title><alt-title alt-title-type="left-running-head">H. Khelfaoui et al.</alt-title><alt-title alt-title-type="right-running-head">Journal of Biomolecular Structure and
Dynamics</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Khelfaoui</surname><given-names>Hadjer</given-names></name><xref ref-type="aff" rid="AF0001">a</xref></contrib><contrib contrib-type="author"><name><surname>Harkati</surname><given-names>Dalal</given-names></name><xref ref-type="aff" rid="AF0001">a</xref><xref ref-type="corresp" rid="AN0001"></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-3187-0888</contrib-id><name><surname>Saleh</surname><given-names>Basil A.</given-names></name><xref ref-type="aff" rid="AF0002">b</xref><xref ref-type="corresp" rid="AN0002"></xref></contrib><aff id="AF0001"><label>a</label><institution>Group of Computational Pharmaceutical Chemistry, LMCE Laboratory, Faculty of Exact and Natural Sciences, Department of Matter Sciences, University of Biskra</institution>,<city>Biskra</city>,<country>Algeria</country></aff><aff id="AF0002"><label>b</label><institution>Department of Chemistry, College of Science, University of Basrah</institution>,<city>Basrah</city>,<country>Iraq</country></aff></contrib-group><author-notes><corresp id="AN0001"><bold>CONTACT</bold> Dalal Harkati <email xlink:href="mailto:d.harkati@univ-biskra.dz">d.harkati@univ-biskra.dz</email><institution>Group of Computational Pharmaceutical Chemistry, LMCE Laboratory, Faculty of
Exact and Natural Sciences, Department of Matter Sciences, University of
Biskra</institution>, <city>Biskra</city><postal-code>07000</postal-code>, <country>Algeria</country></corresp><corresp id="AN0002"> Basil A. Saleh <email xlink:href="mailto:basil.saleh@uobasrah.edu.iq">basil.saleh@uobasrah.edu.iq</email><institution>Department of Chemistry, College of Science, University of
Basrah</institution>, <city>Basrah</city>, <country>Iraq</country></corresp></author-notes><pub-date date-type="pub" publication-format="electronic"><day>5</day><month>8</month><year>2020</year></pub-date><pub-date date-type="collection" publication-format="electronic"><year>2020</year></pub-date><fpage seq="1">1</fpage><lpage>17</lpage><permissions><copyright-statement>© 2020 Informa UK Limited, trading as Taylor & Francis
Group</copyright-statement><copyright-year>2020</copyright-year><copyright-holder>Informa UK Limited, trading as Taylor & Francis
Group</copyright-holder><license><license-p>This article is made available via the PMC Open Access Subset for unrestricted
re-use and analyses in any form or by any means with acknowledgement of the original
source. These permissions are granted for the duration of the COVID-19 pandemic or until
permissions are revoked in writing. Upon expiration of these permissions, PMC is granted
a perpetual license to make this article available via PMC and Europe PMC, consistent
with existing copyright protections.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="TBSD_0_1803967.pdf"></self-uri><abstract><title>Abstract</title><p>The recent new contagion coronavirus 2019 (COVID-19) disease is a new generation of
severe acute respiratory syndrome coronavirus-2 SARS-CoV-2 which infected millions
confirmed cases and hundreds of thousands death cases around the world so far. Molecular
docking combined with molecular dynamics is one of the most important tools of drug
discovery and drug design, which it used to examine the type of binding between the ligand
and its protein enzyme. Global reactivity has important properties, which enable chemists
to understand the chemical reactivity and kinetic stability of compounds. In this study,
molecular docking and reactivity were applied for eighteen drugs, which are similar in
structure to chloroquine and hydroxychloroquine, the potential inhibitors to
angiotensin-converting enzyme (ACE2). Those drugs were selected from DrugBank. The
reactivity, molecular docking and molecular dynamics were performed for two receptors ACE2
and [SARS-CoV-2/ACE2] complex receptor in two active sites to find a ligand, which may
inhibit COVID-19. The results obtained from this study showed that <bold>Ramipril</bold>,
<bold>Delapril</bold> and <bold>Lisinopril</bold> could bind with ACE2 receptor and
[SARS-CoV-2/ACE2] complex better than chloroquine and hydroxychloroquine. This new
understanding should help to improve predictions of the impact of such alternatives on
COVID-19.</p><p>Communicated by Ramaswamy H. Sarma</p></abstract><kwd-group kwd-group-type="author"><title>Keywords</title><kwd>Angiotensin-converting enzyme 2 (ACE2)</kwd><kwd>SARS-CoV-2</kwd><kwd>molecular docking</kwd><kwd>molecular dynamincs simulation</kwd><kwd>global reactivity</kwd></kwd-group><counts><fig-count count="12"></fig-count><table-count count="8"></table-count><page-count count="17"></page-count><word-count count="7795"></word-count></counts></article-meta></front><body><sec id="S0001" disp-level="1"><label>1.</label><title>Introduction</title><p>In late 2019, a new generation of coronavirus appeared in Wuhan City in the Hubei Province
in central China (Wang, Horby, et al., <xref rid="CIT0053" ref-type="bibr">2020</xref>; Zhu
et al., <xref rid="CIT0059" ref-type="bibr">2020</xref>). This virus causes severe acute
respiratory syndrome. The first case was reported on the 8<sup>th</sup> of December 2019 for
many patients lived around the local Huanan Seafood Wholesale Market (Chan et al., <xref rid="CIT0012" ref-type="bibr">2020</xref>). The novel coronavirus was identified from the
throat swab sample of a patient (Wang, Hu, et al., <xref rid="CIT0054" ref-type="bibr">2020</xref>). World Health Organization has abbreviated this novel coronavirus as
2019-nCoV then the pathogen was renamed to SARS-CoV-2(WHO, <xref rid="CIT0055" ref-type="bibr">2020</xref>). After that, World Health Oorganization declared the pandemic
when the virus hit many other countries.</p><p>Human infections by the SARS coronavirus are known to be closely associated with
interactions between the viral spike protein (S-protein) which has favorable binding
affinity for the human Angiotensin-Converting Enzyme 2 (ACE2) (Böhm & Schneider, <xref rid="CIT0008" ref-type="bibr">2005</xref>; Li et al., <xref rid="CIT0034" ref-type="bibr">2005</xref>; Prabakaran et al., <xref rid="CIT0039" ref-type="bibr">2004</xref>;
Veeramachaneni et al., <xref rid="CIT0049" ref-type="bibr">2020</xref>). Several studies
have also provided evidence of the COVID-19 S-protein binding to the ACE2 receptor (Hoffmann
et al., <xref rid="CIT0025" ref-type="bibr">2020</xref>; Lu et al., <xref rid="CIT0035" ref-type="bibr">2020</xref>; Wan et al., <xref rid="CIT0052" ref-type="bibr">2020</xref>).</p><p>Angiotensin-converting enzyme (ACE)-related carboxypeptidase is a zinc metallopeptidase
ectoenzyme, which is predominantly found in the lungs (Skeggs et al., <xref rid="CIT0042" ref-type="bibr">1956</xref>). ACE2, is a type I integral membrane protein, which it consists
of 805 amino acid residues with one Zn<sup>2+</sup> essential for enzyme activity. ACE2 was
implicated in the regulation of heart function and as a functional receptor for the
coronavirus, which is linked to the severe acute respiratory syndrome (SARS). ACE2 is the
cellular receptor for the new coronavirus (SARS-CoV-2) which is causing the serious pandemic
COVID-19 (Hasan et al., <xref rid="CIT0024" ref-type="bibr">2020</xref>; Li et al., <xref rid="CIT0033" ref-type="bibr">2003</xref>; Towler et al., <xref rid="CIT0048" ref-type="bibr">2004</xref>; Yan et al., <xref rid="CIT0056" ref-type="bibr">2020</xref>).</p><p>In a recent study, it was suggested that the 2019-nCoV binds to the human ACE2 receptor via
densely glycosylated spike (S) protein as the initiation step of the entry mechanism to
human cells (Basit et al., <xref rid="CIT0005" ref-type="bibr">2020</xref>; Boopathi et al.,
<xref rid="CIT0009" ref-type="bibr">2020</xref>; Hoffmann et al., <xref rid="CIT0025" ref-type="bibr">2020</xref>). The entry of the virus depends on its binding with the cell
surface units at site 1 and site 2 S1/S2 that contains Zn<sup>+2</sup>, an important
cofactor for numerous viral proteins as well (Te Velthuis et al., <xref rid="CIT0047" ref-type="bibr">2010</xref>). Existence of this metallic ion facilitates the viral
attachment to the surface of target cells. It is well known that zinc ions serve as
intracellular second messenger and may trigger apoptosis or efficiently impair replication
of a number of viruses and this effect may be based on direct inhibition (Alirezaei et al.,
<xref rid="CIT0002" ref-type="bibr">1999</xref>; Frederickson et al., <xref rid="CIT0020" ref-type="bibr">2005</xref>; Lazarczyk & Favre, <xref rid="CIT0032" ref-type="bibr">2008</xref>; Te Velthuis et al., <xref rid="CIT0047" ref-type="bibr">2010</xref>).</p><p>ACE2 exists in every human body but in different quantities (Gurley & Coffman, <xref rid="CIT0022" ref-type="bibr">2008</xref>). Patients, who suffer from hypertension,
diabetes or cardiovascular diseases, have high concentration of ACE2 enzyme in their bodies
(Fang et al., <xref rid="CIT0019" ref-type="bibr">2020</xref>; Gurley & Coffman, <xref rid="CIT0022" ref-type="bibr">2008</xref>; Zhou et al., <xref rid="CIT0058" ref-type="bibr">2020</xref>). These categories of people can be easily infected by
coronavirus compared with children who have low concentration of ACE2 enzyme, their
infection percentage is only 2% (Bunyavanich et al., <xref rid="CIT0010" ref-type="bibr">2020</xref>).</p><p>Blocking the active site of ACE2 by suitable pharmaceutical compound will prevent the virus
entering to the human cells. Therefore, synthesis of such pharmaceutical compound is in
great demand. Many scientists worldwide are trying to synthesise new drugs to stop spreading
the new infectious disease. We think that this route takes a long time, at least 18 months,
until the new vaccine will be available in the markets. Thus, using medicaments already
exist is the shortcut to tackle such issue. In 2005, chloroquine was found as a potent
inhibitor of SARS coronavirus infection and it was suggested to treat the new novel
coronavirus SARS-CoV-2 with hydroxychloroquine (Adeoye et al., <xref rid="CIT0001" ref-type="bibr">2020</xref>; Amin & Abbas, <xref rid="CIT0003" ref-type="bibr">2020</xref>; Böhm & Schneider, <xref rid="CIT0008" ref-type="bibr">2005</xref>; Smith
& Smith, <xref rid="CIT0043" ref-type="bibr">2020</xref>; Vincent et al., <xref rid="CIT0051" ref-type="bibr">2005</xref>). However, due to its cardiotoxicity
hydroxychloroquine has been red flagged by USFDA for use as a prophylactic measure.</p><p>In this study, 18 drugs were selected to evaluate their binding with two receptors ACE2 and
SARS-CoV-2 binding with ACE2 ([SARS-CoV-2/ACE2] complex). These drugs were chosen due to
their similarities in structure with chloroquine and hydroxychloroquine in order to find an
alternative drug for COVID-19.</p></sec><sec id="S0002" disp-level="1"><label>2.</label><title>Materials and methods</title><p>Molecular docking and molecular dynamics simulation was applied to the drugs selected from
the DrugBank database (Wishart et al., <xref rid="CIT0018" ref-type="bibr">2018</xref>) to
study their affinity with coronavirus antibody ACE2 receptor (<bold>PDB ID: 1R42</bold>)
(Towler et al., <xref rid="CIT0048" ref-type="bibr">2004</xref>) and also study their
affinity with the crystal structure of [SARS-CoV-2/ACE2] complex (<bold>PDB ID: 6M0J)</bold>(Lan et al., <xref rid="CIT0031" ref-type="bibr">2020</xref>) to select the most active
drugs that inhibit COVID-19. Global reactivity descriptors of the selected drugs were
calculated to understand their structures, stability and reactivity. The methodology of this
work is illustrated in <xref ref-type="fig" rid="F0001">Figure 1</xref>.</p><fig id="F0001" orientation="portrait" position="float"><label>Figure 1.</label><caption><p>Schematic representation of the docking procedure, analysis of drugs and
reactivity.</p></caption><graphic content-type="color" xlink:href="TBSD_A_1803967_F0001_C"></graphic></fig><sec id="S0002-S2001" disp-level="2"><label>2.1.</label><title>Molecule library preparation</title><p>The chemical structure of drugs inhibitors of ACE2 and similar structures were extracted
from the DrugBank database (Wishart et al., 2018) in MDL Mol format and converted to 3 D
format using Mervin Sketch (<italic>MarvinSketch</italic>, <xref rid="CIT0037" ref-type="bibr">2019</xref>). The structures were pre-optimized with
semi-empirical AM1 method (Stewart, <xref rid="CIT0045" ref-type="bibr">2013</xref>) using
Hyperchem 8.08 software (<italic>HyperChem</italic>, <xref rid="CIT0026" ref-type="bibr">2009</xref>). The structures were optimized using density functional
theory DFT method by employing the B3LYP/6-31G basis set (Becke, <xref rid="CIT0006" ref-type="bibr">1997</xref>; Frisch et al., <xref rid="CIT0021" ref-type="bibr">2009</xref>) to obtain the most stable conformation, which was also used to calculate
the global reactivity descriptors through Gaussian 09 (Frisch et al., <xref rid="CIT0021" ref-type="bibr">2009</xref>). The convergent value of maximum force,
root-mean-square (RMS) force, maximum displacement and RMS displacement are set by default
and achieved “YES”. All values are positive after calculation vibrational frequencies to
drugs, those results indicate that the drugs are stable (Cavalli et al., <xref rid="CIT0011" ref-type="bibr">2006</xref>). The optimized structures were combined in
one database on MOE software (<italic>Molecular Operating Environment
(MOE)</italic>, <xref rid="CIT0038" ref-type="bibr">2015</xref>) in order to study the
affinity of ligands (<xref ref-type="fig" rid="F0002">Figure 2</xref> and <xref rid="t0001" ref-type="table">Table 1</xref>).</p><fig id="F0002" orientation="portrait" position="float"><label>Figure 2.</label><caption><p>The structures of selected drugs.</p></caption><graphic content-type="black-white" xlink:href="TBSD_A_1803967_F0002_B"></graphic></fig><table-wrap id="t0001" orientation="portrait" position="float"><label>Table 1.</label><caption><p>Names, accessions numbers and clinical indication of drugs.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="1*"></col><col width="1*"></col><col width="1*"></col></colgroup><thead><tr><th align="left">Drugs names</th><th align="center">Accessions Numbers</th><th align="center">Clinical Indication</th></tr></thead><tbody valign="top"><tr><td align="left"><bold>Chloroquine</bold></td><td align="left">DB00608 (APRD00468)</td><td align="left">Anti-malarial<break></break>Anti-inflammatory<break></break>Anti-parasitic</td></tr><tr><td align="left"><bold>Hydroxychloroquine</bold></td><td align="left">DB01611</td><td align="left">Anti-malarial<break></break>Anti-parasitic<break></break>Anti-rheumatic<break></break>Anti-infective</td></tr><tr><td align="left"><bold>Quinacrine</bold></td><td align="left">DB01103 (APRD00317)</td><td align="left">Anti-infective<break></break>Anti-malarial<break></break>Anti-parasitic</td></tr><tr><td align="left"><bold>Quinacrine
mustard</bold></td><td align="left">DB02240 (EXPT02733)</td><td align="left">Anti-parasitic</td></tr><tr><td align="left"><bold>Piperaquine</bold></td><td align="left">DB13941</td><td align="left">Anti-infective<break></break>Anti-malarial<break></break>Anti-parasitic</td></tr><tr><td align="left"><bold>Ramipril</bold></td><td align="left">DB00178 (APRD00009)</td><td align="left">Angiotensin-Converting Enzyme
inhibitors<break></break>Anti-hypertensive<break></break>Cardiovascular</td></tr><tr><td align="left"><bold>Trandolapril</bold></td><td align="left">DB00519 (APRD01269)</td><td align="left">Angiotensin-Converting Enzyme
inhibitors<break></break>Anti-hypertensive<break></break>Cardiovascular</td></tr><tr><td align="left"><bold>Ramiprilat</bold></td><td align="left">DB14208</td><td align="left">Angiotensin-Converting Enzyme
inhibitors<break></break>Anti-hypertensive<break></break>Cardiovascular</td></tr><tr><td align="left"><bold>Enalapril</bold></td><td align="left">DB00584 (APRD00510)</td><td align="left">Angiotensin-Converting Enzyme
inhibitors<break></break>Anti-hypertensive<break></break>Cardiovascular</td></tr><tr><td align="left"><bold>Trandolaprilat</bold></td><td align="left">DB14209</td><td align="left">Angiotensin-Converting Enzyme
inhibitors</td></tr><tr><td align="left"><bold>Lisinopril</bold></td><td align="left">DB00722 (APRD00560)</td><td align="left">Angiotensin-Converting Enzyme
inhibitors<break></break>Anti-hypertensive<break></break>Cardiovascular</td></tr><tr><td align="left"><bold>Perindopril</bold></td><td align="left">DB00790 (APRD01178)</td><td align="left">Angiotensin-Converting Enzyme
inhibitors<break></break>Anti-hypertensive<break></break>Cardiovascular</td></tr><tr><td align="left"><bold>Enalaprilat</bold></td><td align="left">DB09477</td><td align="left">Angiotensin-Converting Enzyme
inhibitors<break></break>Anti-hypertensive<break></break>Cardiovascular<break></break>Decreased blood
pressure</td></tr><tr><td align="left"><bold>Delapril</bold></td><td align="left">DB13312</td><td align="left">Angiotensin-Converting Enzyme
inhibitors<break></break>Anti-hypertensive<break></break>Cardiovascular</td></tr><tr><td align="left"><bold>ORE-1001</bold></td><td align="left">DB12271 (DB06387)</td><td align="left">Angiotensin-Converting Enzyme
inhibitors</td></tr><tr><td align="left"><bold><italic toggle="yes">N</italic>-(2-Aminoethyl)-1-aziridineethanamine</bold></td><td align="left">DB15643</td><td align="left">Angiotensin-Converting Enzyme
inhibitors</td></tr><tr><td align="left"><bold>Triethylenetetramine</bold></td><td align="left">DB06824</td><td align="left">Copper chelator agent</td></tr><tr><td align="left"><bold>Piperazine</bold></td><td align="left">DB00592 (APRD00225,
DB11514)</td><td align="left">Anti-parasitic<break></break>Anti-infective</td></tr></tbody></table></table-wrap></sec><sec id="S0002-S2002" disp-level="2"><label>2.2.</label><title>Receptor preparation</title><p>The crystal structure of the angiotensin-converting enzyme related carboxypeptidase ACE2
receptor <bold>(PDB ID: 1R42)</bold> (Towler et al., <xref rid="CIT0048" ref-type="bibr">2004</xref>) and Crystal structure [SARS-CoV-2/ACE2] complex <bold>(PDB ID:
6M0J)</bold> (Lan et al., <xref rid="CIT0031" ref-type="bibr">2020</xref>) were found in
the Protein Data Bank. The enzymes were prepared by removing the <italic>N</italic>-acetyl-D-glucosamine in sequence editor. Because the water molecule in the
active site of the target enzyme plays an important role, it was inserted in the active
sites to ensure making a hydrogen bond between the ligand and the target (Böhm &
Schneider, <xref rid="CIT0008" ref-type="bibr">2005</xref>; Klebe, <xref rid="CIT0030" ref-type="bibr">2006</xref>; Marechal, <xref rid="CIT0036" ref-type="bibr">2007</xref>).</p><p>Because Zn<sup>2+</sup> is an important cofactor for many viral proteins, Zn<sup>2+</sup>can inhibit the replication of ARN polymerase, two active sites containing zinc
(Zn<sup>2+</sup>) in 1R42 and 6M0J enzymes were chosen as shown in <xref ref-type="fig" rid="F0003">Figures 3</xref> and <xref ref-type="fig" rid="F0004">4</xref> respectively
(Te Velthuis et al., <xref rid="CIT0047" ref-type="bibr">2010</xref>). After that, the
protein structure was prepared by correcting the missing bonds, which were broken in X-ray
diffraction, and then the hydrogen atoms were added (<xref rid="t0002" ref-type="table">Table 2</xref>).</p><fig id="F0003" orientation="portrait" position="float"><label>Figure 3.</label><caption><p>Crystal structure of native human Angiotensin Converting Enzyme-related
carboxypeptidase (ACE2) (<bold>PDB ID: 1R42</bold>).</p></caption><graphic content-type="color" xlink:href="TBSD_A_1803967_F0003_C"></graphic></fig><fig id="F0004" orientation="portrait" position="float"><label>Figure 4.</label><caption><p>Crystal structure of [SARS-CoV-2/ACE2] complex <bold>(PDB ID: 6M0J)</bold>.</p></caption><graphic content-type="color" xlink:href="TBSD_A_1803967_F0004_C"></graphic></fig><table-wrap id="t0002" orientation="portrait" position="float"><label>Table 2.</label><caption><p>Binding sites residues used as input for receptor grid generation during Induced Fit
Docking.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="1*"></col><col width="1*"></col><col width="1*"></col></colgroup><thead><tr><th align="left">Receptors</th><th align="center">Sites</th><th align="center">Residues</th></tr></thead><tbody valign="top"><tr><td rowspan="2"><bold>1R42</bold></td><td align="left"><bold>Site 1</bold></td><td align="left"><bold>1</bold>: (Arg73, Phe274, Pro346,
Asp367, Leu370, Thr371, His374, Glu375, Glu402, Glu406, Ser409, Leu410, Ala413,
Phe438, Gln442, Thr445, Ile446, Thr449, Thr453, Phe512, Tyr515, Arg518, Thr519,
Gln522) <bold>2</bold> : <bold>(Zn804)</bold></td></tr><tr><td align="left"><bold>Site 2</bold></td><td align="left"><bold>1</bold> : (Phe40, Pro346, Thr347,
Ala348, Asp350, Gly352, His374, Glu375, His378, Asp382, Tyr385, Phe390, Arg393,
Asn394, His401, Glu402) <bold>2: (Zn804)</bold></td></tr><tr><td rowspan="2"><bold>6M0J</bold></td><td align="left"><bold>Site 1</bold></td><td align="left"><bold>1</bold>: (Tyr127, Asn149, Asp269,
Trp271, Arg273, Phe274, Thr276, Tyr279, Lys288, Pro289, Asn290, Ile291, Asp292,
Thr294, His345, Pro346, Thr365, Met366, Asp367, Leu370, Thr371, His374, Glu375,
Glu402, Glu406, Ser409, Leu410, Ala413, Thr414, Pro415, Leu418 Phe428, Glu430,
Asp431, Thr434, Glu435, Asn437, Phe438, Lys441, Gln442, Thr445, Ile446, Thr449,
Leu503, Phe504, His505, Tyr515, Arg518, Thr519, Gln522, Phe523, His540)
<bold>3</bold> :<bold>(Zn901)</bold></td></tr><tr><td align="left"><bold>Site 2</bold></td><td align="left"><bold>1: (</bold>His345, Pro346, Thr347,
Ala348, Glu375, His378, Asp382, His401, Glu402) <bold>3
:(Zn901)</bold></td></tr></tbody></table></table-wrap></sec></sec><sec id="S0003" disp-level="1"><label>3.</label><title>Molecular docking</title><p>All the docking and scoring calculations were performed using the molecular operation
environment software (MOE) (<italic>Molecular Operating Environment
(MOE)</italic>, 2015). The crystal structure of human angiotensin converting enzyme (PDB
entry: 1R42) (Towler et al., <xref rid="CIT0048" ref-type="bibr">2004</xref>) at a
resolution of 2.20 Å and the crystal structure of [SARS-CoV-2/ACE2] complex (PDB entry:
6M0J) (Lan et al., <xref rid="CIT0031" ref-type="bibr">2020</xref>) at a resolution of
2.45 Å were obtained from the Protein Data Bank (Berman et al., <xref rid="CIT0007" ref-type="bibr">2020</xref>) .A resolution between 1.5 and 2.5 Å is considered as a good
quality for docking studies (Didierjean & Tête-Favier, <xref rid="CIT0016" ref-type="bibr">2016</xref>; Venugopal et al., <xref rid="CIT0050" ref-type="bibr">2008</xref>). It is known that the best score of RMSD values should be near to 2 Å with
an energy score less or equal to −7 Kcal/mol (Kellenberger et al., <xref rid="CIT0028" ref-type="bibr">2004</xref>; Ramalho et al., <xref rid="CIT0040" ref-type="bibr">2009</xref>). These two values are often used as criterion to validate the result of the
molecular docking.</p></sec><sec id="S0004" disp-level="1"><label>4.</label><title>Global reactivity descriptors</title><p>Global reactivity indices are the most relevant traits, which can be derived from the
conceptual density functional theory (DFT). They have important properties which enable us
to understand the chemical reactivity and kinetic stability of compounds (Shahab et al.,
<xref rid="CIT0041" ref-type="bibr">2016</xref>). The global reactivity descriptors can be
described by energy of the highest occupied molecular orbital
<bold>(E<sub>HOMO</sub>)</bold>, energy of the lowest unoccupied molecular orbital
<bold>(E<sub>LUMO</sub>)</bold>, energy gap <bold>(ΔE)</bold>, global electrophilicity
<bold>(ω)</bold>, chemical potential <bold>(µ)</bold>, chemical hardness <bold>(η)</bold>,
chemical softness <bold>(S)</bold> and nucleophilicity <bold>(N)</bold> (Defranceschi &
C. Le Bris, <xref rid="CIT0014" ref-type="bibr">2000</xref>; Domingo et al., <xref rid="CIT0017" ref-type="bibr">2016</xref>; Harkati et al., <xref rid="CIT0023" ref-type="bibr">2017</xref>; Zekri et al., <xref rid="CIT0057" ref-type="bibr">2020</xref>).
Those descriptors were calculated at B3LYP/6-31G using the following formulas:</p><p><bold>(</bold>ΔE = E<sub>LUMO</sub>-E<sub>HOMO</sub><bold>)</bold>, <bold>(</bold>ω =
µ<sup>2</sup>/2η<bold>)</bold>, <bold>(</bold>µ =
(E<sub>LUMO</sub>+E<sub>HOMO</sub>)/2<bold>)</bold>, <bold>(</bold>η = (E<sub>LUMO</sub>-
E<sub>HOMO</sub>)/2<bold>)</bold>, <bold>(</bold><italic>S</italic> = 1/(2
η)<bold>)</bold>, <bold>(</bold>N = E<sub>HOMO</sub> (Nucleophile) – E<sub>HOMO</sub>(TCE)<bold>)</bold>.</p><p>In this study, the global reactivity descriptors were calculated to compounds that have
best result in docking with ACE2 and [SARS-CoV-2/ACE2] complex.</p></sec><sec id="S0005" disp-level="1"><label>5.</label><title>Molecular dynamics simulation</title><p>The molecular dynamics (MD) simulation study was carried out for the most promising drugs
<bold>Delapril</bold>, <bold>Lisinopril</bold> and <bold>Ramipril</bold> to target
[SARS-CoV-2/ACE2] complex (<bold>6M0J</bold>) using standard default parameter setting in
the MOE software (<italic>Molecular Operating Environment (MOE)</italic>,
2015).</p><p>There are four algorithms implemented in MOE software for MD simulations; the
Nosé-Poincaré-Andesen (NPA), the Nosé-Hoover-Andersen (NHA), Berendsen velocity/position
(BER) and Nanoscale Molecular Dynamics (NAMD). In this study, the NPA is: the most precise
and the most sensitive, was used to study the molecular dynamics of ligands (Sturgeon &
Laird, <xref rid="CIT0046" ref-type="bibr">2000</xref>). In MD calculations, MMFF94x force
field, sphere shape, water as a solvent, six margins and delete far existing solvent with
distance greater than four Å were selected to optimize the system.</p></sec><sec id="S0006" disp-level="1"><label>6.</label><title>Results and discussion</title><sec id="S0006-S2001" disp-level="2"><label>6.1.</label><title>Molecular docking</title><p>Molecular docking was run for 18 ligands against the [SARS-CoV-2/ACE2] complex and the
ACE2 receptor.</p><sec id="S0006-S2001-S3001" disp-level="3"><label>6.1.1.</label><title>The binding affinities of the drugs into ACE2 active sites</title><p><xref rid="t0003" ref-type="table">Tables 3</xref> and <xref rid="t0004" ref-type="table">4</xref> present the results of docking the drugs in 1R42 at two selected
pockets S1 and S2 respectively. The results, as shown in <xref rid="t0003" ref-type="table">Table 3</xref>, indicate that only seven ligands have an interaction with
the receptor in pocket S1. <bold>Delapril</bold> has the best docking score
(-6.9809 kcal/mol) followed by <bold>Lisinopril</bold> (-6.6886 kcal/mol)) with RMSDs
2.2570 Å and 1.5417 Å respectively. On the other hand, <bold>Ramiprilat</bold> and
<bold>Piperaquine</bold> had RMSDs more than 3 Å and <bold>Trandolaprilat</bold>,
<bold>Chloroquine</bold> and <bold>Perindopril</bold> had RMSDs less than 1.5 Å, which
this is inadequate .</p><table-wrap id="t0003" orientation="portrait" position="float"><label>Table 3.</label><caption><p>The results obtained from docking of Drugs with <bold>1R42</bold> in <bold>site
1</bold>.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col></colgroup><thead><tr><th rowspan="2" align="left">Drugs</th><th rowspan="2" align="center">S score
(kcal/mol)</th><th rowspan="2" align="center">RMSD (Å)</th><th colspan="6" align="center">Bonds
between atoms of compounds and residues of active site 1 of 1R42<hr></hr></th></tr><tr><th align="center">Atom of compound</th><th align="center">Atom of receptor</th><th align="center">Involved receptor
residues</th><th align="center">Type of interaction
bond</th><th align="center">Distance (Å)</th><th align="center">E (kcal/mol)</th></tr></thead><tbody valign="top"><tr><td align="left"><bold>Chloroquine</bold></td><td align="center">−6.1074</td><td align="center">1.1063</td><td align="center">N-1</td><td align="center">O</td><td align="center">H<sub>2</sub>O 932</td><td align="center">H-acceptor</td><td align="center">2.79</td><td align="center">−1</td></tr><tr><td rowspan="5"><bold>Delapril</bold></td><td rowspan="5">−6.9809</td><td rowspan="5" align="char" char=".">2.2570</td><td align="center">O-31</td><td align="center">OG</td><td align="center">Ser 409</td><td align="center">H-donor</td><td align="center">3.08</td><td align="center">−0.7</td></tr><tr><td align="center">O-24</td><td align="center">O</td><td align="center">H<sub>2</sub>O 932</td><td rowspan="2">H-acceptor</td><td align="center">2.84</td><td align="center">−1.3</td></tr><tr><td align="center">O-25</td><td align="center">NE2</td><td align="center">Gln 442</td><td align="center">3.16</td><td align="center">−1.7</td></tr><tr><td align="center">C-43</td><td align="center">5-ring</td><td align="center">His 374</td><td align="center">H-pi</td><td align="center">3.71</td><td align="center">−1</td></tr><tr><td align="center">6-ring</td><td align="center">O</td><td align="center">H<sub>2</sub>O 932</td><td align="center">pi-H</td><td align="center">4.08</td><td align="center">−1.2</td></tr><tr><td align="left"><bold>Lisinopril</bold></td><td align="center">−6.6886</td><td align="center">1.5417</td><td align="center">O-5</td><td align="center">O</td><td align="center">H<sub>2</sub>O 932</td><td align="center">H-donor</td><td align="center">3.24</td><td align="center">−0.6</td></tr><tr><td align="left"><bold>Perindopril</bold></td><td align="center">−6.5856</td><td align="center">1.1260</td><td align="center">O-42</td><td align="center">NE2</td><td align="center">Gln 442</td><td align="center">H-acceptor</td><td align="center">3.3</td><td align="center">−0.8</td></tr><tr><td align="left"><bold>Piperaquine</bold></td><td align="center">−6.6531</td><td align="center">3.2826</td><td align="center">6-ring</td><td align="center">CD</td><td align="center">Pro 346</td><td align="center">pi-H</td><td align="center">4.35</td><td align="center">−0.8</td></tr><tr><td rowspan="4"><bold>Ramiprilat</bold></td><td rowspan="4">−6.6703</td><td rowspan="4" align="char" char=".">4.3112</td><td align="center">O-46</td><td align="center">O</td><td align="center">H<sub>2</sub>O 1075</td><td rowspan="3" align="center">H-donor</td><td align="center">2.98</td><td align="center">−1.6</td></tr><tr><td rowspan="2" align="center">O-51</td><td align="center">OE1</td><td align="center">Glu 406</td><td align="center">2.9</td><td align="center">−2.3</td></tr><tr><td align="center">O</td><td align="center">H<sub>2</sub>O 1099</td><td align="center">2.89</td><td align="center">−1.1</td></tr><tr><td align="center">O-45</td><td align="center">NE2</td><td align="center">Gln 442</td><td align="center">H-acceptor</td><td align="center">3</td><td align="center">−1</td></tr><tr><td align="left"><bold>Trandolaprilat</bold></td><td align="center">−6.7507</td><td align="center">1.4433</td><td align="center">N-45</td><td align="center">OE1</td><td align="center">Gln 442</td><td align="center">H-donor</td><td align="center">3.09</td><td align="center">−1.6</td></tr></tbody></table></table-wrap><table-wrap id="t0004" orientation="portrait" position="float"><label>Table 4.</label><caption><p>The results obtained from docking of Drugs with <bold>1R42</bold> in <bold>site
2</bold>.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col></colgroup><thead><tr><th rowspan="2" align="left">Drug</th><th rowspan="2" align="center">S score
(kcal/mol)</th><th rowspan="2" align="center">RMSD (Å)</th><th colspan="6" align="center">Bonds
between atoms of compounds and residues of active site 2 of 1R42<hr></hr></th></tr><tr><th align="center">Atom of compound</th><th align="center">Atom of receptor</th><th align="center">Involved receptor
residues</th><th align="center">Type of interaction
bond</th><th align="center">Distance (Å)</th><th align="center">E (kcal/mol)</th></tr></thead><tbody valign="top"><tr><td rowspan="2"><bold>Chloroquine</bold></td><td rowspan="2">−5.5271</td><td rowspan="2" align="char" char=".">1.3462</td><td align="center">N-17</td><td align="center">O</td><td align="center">Ala 348</td><td align="center">H-donor</td><td align="center">3.05</td><td align="center">−2</td></tr><tr><td align="center">6-ring</td><td align="center">6-ring</td><td align="center">Trp 349</td><td align="center">pi-pi</td><td align="center">3.96</td><td align="center">0</td></tr><tr><td align="left"><bold>Delapril</bold></td><td align="center">−6.5831</td><td align="center">2.0115</td><td align="center">O-25</td><td align="center">O</td><td align="center">H<sub>2</sub>O 894</td><td align="center">H-acceptor</td><td align="center">2.9</td><td align="center">−0.8</td></tr><tr><td align="left"><bold>Enalapril</bold></td><td align="center">−6.1282</td><td align="center">2.6836</td><td align="center">C-28</td><td align="center">5-ring</td><td align="center">Trp 349</td><td align="center">H-pi</td><td align="center">3.86</td><td align="center">−0.7</td></tr><tr><td rowspan="2"><bold>Enalaprilat</bold></td><td rowspan="2">−5.9910</td><td rowspan="2" align="char" char=".">1.2547</td><td align="center">O-40</td><td align="center">N</td><td align="center">Asp 350</td><td align="center">H-acceptor</td><td align="center">3.34</td><td align="center">−1.3</td></tr><tr><td align="center">C-45</td><td align="center">5-ring</td><td align="center">Trp 349</td><td align="center">H-pi</td><td align="center">3.46</td><td align="center">−2.6</td></tr><tr><td rowspan="2"><bold>Hydroxychloroquine</bold></td><td rowspan="2">−5.6369</td><td rowspan="2" align="char" char=".">1.8041</td><td align="center">O-2</td><td align="center">O</td><td align="center">Arg 393</td><td align="center">H-donor</td><td align="center">2.99</td><td align="center">−0.8</td></tr><tr><td align="center">N-7</td><td align="center">N</td><td align="center">Asp 350</td><td align="center">H-acceptor</td><td align="center">3.13</td><td align="center">−1.3</td></tr><tr><td align="left"><bold>Lisinopril</bold></td><td align="center">−5.6358</td><td align="center">1.7176</td><td align="center">O-5</td><td align="center">O</td><td align="center">Arg 393</td><td align="center">H-donor</td><td align="center">3.19</td><td align="center">−2.4</td></tr><tr><td align="left"><bold>Perindopril</bold></td><td align="center">−6.2821</td><td align="center">1.1895</td><td align="center">O-23</td><td align="center">5-ring</td><td align="center">His 401</td><td align="center">H-pi</td><td align="center">3.51</td><td align="center">−0.7</td></tr><tr><td align="left"><bold>Piperazine</bold></td><td align="center">−3.4925</td><td align="center">2.5032</td><td align="center">C-5</td><td align="center">5-ring</td><td align="center">Trp 349</td><td align="center">H-pi</td><td align="center">3.86</td><td align="center">−0.9</td></tr><tr><td rowspan="2"><bold>Quinacrine</bold></td><td rowspan="2">−5.9184</td><td rowspan="2" align="char" char=".">1.1669</td><td align="center">C-37</td><td align="center">6-ring</td><td align="center">Trp 349</td><td rowspan="2" align="center">H-pi</td><td align="center">4.42</td><td align="center">−0.6</td></tr><tr><td align="center">C-37</td><td align="center">5-ring</td><td align="center">Trp 349</td><td align="center">3.8</td><td align="center">−1.4</td></tr><tr><td rowspan="2"><bold>Ramipril</bold></td><td rowspan="2">−6.1181</td><td rowspan="2" align="char" char=".">1.5054</td><td align="center">O-46</td><td align="center">N</td><td align="center">Asp 350</td><td rowspan="2">H-acceptor</td><td align="center">3</td><td align="center">−3.2</td></tr><tr><td align="center">O-58</td><td align="center">O</td><td align="center">H<sub>2</sub>O 892</td><td align="center">3.07</td><td align="center">−1</td></tr><tr><td rowspan="4"><bold>Ramiprilat</bold></td><td rowspan="4">−5.8613</td><td rowspan="4" align="char" char=".">1.8268</td><td align="center">O-51</td><td align="center">O</td><td align="center">Leu 391</td><td align="center">H-donor</td><td align="center">2.92</td><td align="center">−1.4</td></tr><tr><td align="center">O-46</td><td align="center">ND2</td><td align="center">Asn 394</td><td rowspan="3">H-acceptor</td><td align="center">3.02</td><td align="center">−0.8</td></tr><tr><td align="center">O-49</td><td align="center">NZ</td><td align="center">Lys 562</td><td align="center">3.01</td><td align="center">−5.7</td></tr><tr><td align="center">O-54</td><td align="center">ND2</td><td align="center">Asn 394</td><td align="center">2.85</td><td align="center">−0.9</td></tr><tr><td align="left"><bold>Trandolaprilat</bold></td><td align="center">−5.7171</td><td align="center">2.8424</td><td align="center">O-53</td><td align="center">O</td><td align="center">H<sub>2</sub>O 952</td><td align="center">H-donor</td><td align="center">2.97</td><td align="center">−2.2</td></tr></tbody></table></table-wrap><p>Interactions were further examined for bond lengths and hydrogen bonds in site 1 and
were illustrated in <xref ref-type="fig" rid="F0005">Figure 5</xref>. The results from
this <xref ref-type="fig" rid="F0005">Figure 5</xref> showed that <bold>Delapril</bold>interacts with three amino acids residues in three different interactions; H-donor with
amino acid Ser409, H-acceptor with Gln442, H-pi with His374 as well as two H-acceptor
and pi-H interactions with the water. The distance and energy binding of interaction are
listed in <xref rid="t0003" ref-type="table">Table 3</xref>.</p><fig id="F0005" orientation="portrait" position="float"><label>Figure 5.</label><caption><p>Compounds binding with <bold>1R42</bold> in site <bold>1</bold>.</p></caption><graphic content-type="color" xlink:href="TBSD_A_1803967_F0005_C"></graphic></fig><p>From <xref rid="t0004" ref-type="table">Table 4</xref>, the docking results in pocket
S2, it can be noticed that <bold>Delapril</bold> had the lowest docking score
(-6.5831 kcal/mol) with RMSD (2.0115 Å) followed by <bold>Perindopril</bold>,
<bold>Ramipril</bold> and <bold>Chloroquine</bold> with docking score and RMSD values
of (-6.2821 Kcal/mol, 1.1895 Å), (-6.1181 Kcal/mol, 1.5054 Å) and (-5.5271 Kcal/mol,
1.3462 Å) respectively. Even in this site, <bold>Chloroquine</bold> had a good score but
actually it had an inadequate RMSD value (1.3462 Å), which is less than the accepted
limit 1.5 Å. The same things can be said for <bold>Enalaprilat</bold>,
<bold>Perindopril</bold> and <bold>Quinacrine</bold>.</p><p>The interactions of drugs with site 2 were also examined and depicted in <xref ref-type="fig" rid="F0006">Figure 6</xref>. <xref ref-type="fig" rid="F0006">Figure
6</xref> shows that <bold>Delapril</bold> had H-acceptor interaction with water, while
<bold>Perindopril</bold> had H-pi interaction with amino acid His401. Meanwhile,
<bold>Ramipril</bold> had H-acceptor interaction with amino acid Asp350 and H-acceptor
with water and <bold>Chloroquine</bold> had H-donor interaction with amino acid Ala348
and pi-pi interaction with Trp349. The distance and the energy binding are presented in
<xref rid="t0004" ref-type="table">Table 4</xref>.</p><fig id="F0006" orientation="portrait" position="float"><label>Figure 6.</label><caption><p>Compounds binding with <bold>1R42</bold> in site <bold>2</bold>.</p></caption><graphic content-type="color" xlink:href="TBSD_A_1803967_F0006_C"></graphic></fig></sec><sec id="S0006-S2001-S3002" disp-level="3"><label>6.1.2.</label><title>The binding affinities of the drugs into [SARS-CoV-2/ACE2] complex active
sites</title><p><xref rid="t0005" ref-type="table">Tables 5</xref> and <xref rid="t0006" ref-type="table">6</xref> show the results of docking of the drugs in 6M0J at two selected
pockets S1 and S2 respectively. The results in pocket S1 revealed that
<bold>Piperaquine</bold> had the lowest docking score (-8.6132 Kcal/mol) and RMSD
(2.3325 Å) compared with <bold>Delapril</bold> and <bold>Hydroxychloroquine</bold>,
which they had energy scores and RMSD values of (-7.5271 Kcal/mol, 2.1735 Å) and
(-7.2272 Kcal/mol, 2.1035 Å) respectively. In spite of <bold>Delapril</bold> and
<bold>Hydroxychloroquine</bold> did not have the lowest score, they have the best RMSD
values. <bold>Lisinopril</bold> and <bold>Quinacrine Mustard</bold> had RMSD value less
than 1.5 Å.</p><table-wrap id="t0005" orientation="portrait" position="float"><label>Table 5.</label><caption><p>The results obtained from docking of Drugs with <bold>6M0J</bold> in site
<bold>1</bold>.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col></colgroup><thead><tr><th rowspan="2" align="left">Drugs</th><th rowspan="2" align="center">S score
(kcal/mol)</th><th rowspan="2" align="center">RMSD (Å)</th><th colspan="6" align="center">Bonds
between atoms of compounds and residues of active site 1 of 6M0J<hr></hr></th></tr><tr><th align="center">Atom of compound</th><th align="center">Atom of receptor</th><th align="center">Involved receptor
residues</th><th align="center">Type of interaction
bond</th><th align="center">Distance (Å)</th><th align="center">E (kcal/mol)</th></tr></thead><tbody valign="top"><tr><td align="left"><bold>Chloroquine</bold></td><td align="center">−6.8442</td><td align="center">1.9853</td><td align="center">6-ring</td><td align="center">6-ring</td><td align="center">Phe 438</td><td align="center">pi-pi</td><td align="center">3.37</td><td align="center">0</td></tr><tr><td rowspan="11"><bold>Delapril</bold></td><td rowspan="11">−7.5271</td><td rowspan="11" align="center">2.1735</td><td align="center">O-31</td><td align="center">OE2</td><td align="center">Glu 375</td><td align="center">H-donor</td><td align="center">3.01</td><td align="center">−4.5</td></tr><tr><td align="center">O-25</td><td align="center">NH2</td><td align="center">Arg 514</td><td align="center">H-acceptor</td><td align="center">3.04</td><td align="center">−1.4</td></tr><tr><td align="center">O-26</td><td align="center">ZN</td><td align="center">Zn 901</td><td rowspan="4" align="center">metallic</td><td align="center">1.96</td><td align="center">−2.1</td></tr><tr><td rowspan="6" align="center">Zn-901</td><td align="center">NE2</td><td align="center">His 374</td><td align="center">2.4</td><td align="center">−3.2</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td align="center">2.27</td><td align="center">−5.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−5.6</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td rowspan="3" align="center">ionic</td><td align="center">2.27</td><td align="center">−11.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−14.4</td></tr><tr><td align="center">OE2</td><td align="center">Glu 402</td><td align="center">3.13</td><td align="center">−3.7</td></tr><tr><td rowspan="2" align="center">6-ring</td><td align="center">OH</td><td align="center">Tyr 515</td><td align="center">Pi-H</td><td align="center">3.38</td><td align="center">−0.9</td></tr><tr><td align="center">6-ring</td><td align="center">Tyr 510</td><td align="center">pi-pi</td><td align="center">3.93</td><td align="center">0</td></tr><tr><td align="left"><bold>Enalapril</bold></td><td align="center">−7.8671</td><td align="center">1.9897</td><td align="center">O-22</td><td align="center">O</td><td align="center">Pro 289</td><td align="center">H-donor</td><td align="center">3.39</td><td align="center">−0.8</td></tr><tr><td rowspan="2"><bold>Enalaprilat</bold></td><td rowspan="2">−6.9279</td><td rowspan="2" align="center">1.8459</td><td rowspan="2" align="center">O-44<break></break>6-ring</td><td align="center">NZ</td><td align="center">Lys 441</td><td align="center">H-acceptor</td><td align="center">3.16</td><td align="center">−8.4</td></tr><tr><td align="center">6-ring</td><td align="center">Phe 438</td><td align="center">pi-pi</td><td align="center">3.73</td><td align="center">0</td></tr><tr><td rowspan="2"><bold>Hydroxychloroquine</bold></td><td rowspan="2">−7.2272</td><td rowspan="2" align="center">2.1035</td><td align="center">6-ring</td><td align="center">CB</td><td align="center">Phe 438</td><td align="center">pi-H</td><td align="center">3.82</td><td align="center">−0.8</td></tr><tr><td align="center">6-ring</td><td align="center">6-ring</td><td align="center">Phe 438</td><td align="center">pi-pi</td><td align="center">3.81</td><td align="center">0</td></tr><tr><td rowspan="3"><bold>Lisinopril</bold></td><td rowspan="3">−7.5918</td><td rowspan="3" align="center">1.3368</td><td align="center">N-11</td><td align="center">NE2</td><td align="center">Gln 442</td><td align="center">H-acceptor</td><td align="center">3.18</td><td align="center">−2.8</td></tr><tr><td rowspan="2" align="center">6-ring<break></break>6-ring</td><td align="center">CA</td><td align="center">Asn 290</td><td rowspan="2" align="center">Pi-H</td><td align="center">4.07</td><td align="center">−0.8</td></tr><tr><td align="center">N</td><td align="center">Ile 291</td><td align="center">4.22</td><td align="center">−0.9</td></tr><tr><td rowspan="3"><bold>ORE-1001</bold></td><td rowspan="3">−7.3872</td><td rowspan="3" align="center">1.5557</td><td align="center">Cl</td><td align="center">O</td><td align="center">Leu 410</td><td align="center">H-donor</td><td align="center">3.49</td><td align="center">−0.8</td></tr><tr><td align="center">5-ring</td><td align="center">CB</td><td align="center">Phe 438</td><td align="center">pi-H</td><td align="center">4.43</td><td align="center">−0.7</td></tr><tr><td align="center">6-ring</td><td align="center">6-ring</td><td align="center">Phe 438</td><td align="center">pi-pi</td><td align="center">3.37</td><td align="center">0</td></tr><tr><td align="left"><bold>Perindopril</bold></td><td align="center">−6.4327</td><td align="center">2.4655</td><td align="center">N-26</td><td align="center">O</td><td align="center">Ile 291</td><td align="center">H-donor</td><td align="center">3.21</td><td align="center">−0.8</td></tr><tr><td align="left"><bold>Piperaquine</bold></td><td align="center">−8.6132</td><td align="center">2.3325</td><td align="center">6-ring</td><td align="center">6-ring</td><td align="center">Phe 438</td><td align="center">pi-pi</td><td align="center">3.35</td><td align="center">0</td></tr><tr><td rowspan="2"><bold>Quinacrine</bold></td><td rowspan="2">−8.2350</td><td rowspan="2" align="center">1.6346</td><td rowspan="2" align="center">6-ring
6-ring</td><td align="center">N</td><td align="center">Ile 291</td><td rowspan="2" align="center">pi-H</td><td align="center">4.81</td><td align="center">−0.6</td></tr><tr><td align="center">N</td><td align="center">Ile 291</td><td align="center">3.98</td><td align="center">−1.1</td></tr><tr><td rowspan="3"><bold>Quinacrine
Mustard</bold></td><td rowspan="3">−7.8570</td><td rowspan="3" align="center">1.4398</td><td align="center">Cl-58</td><td align="center">SD</td><td align="center">Met 366</td><td align="center">H-donor</td><td align="center">3.74</td><td align="center">−0.4</td></tr><tr><td rowspan="2" align="center">6-ring<break></break>6-ring</td><td align="center">N</td><td align="center">Ile 291</td><td align="center">pi-H</td><td align="center">3.98</td><td align="center">−1.4</td></tr><tr><td align="center">6-ring</td><td align="center">Phe 438</td><td align="center">pi-pi</td><td align="center">3.58</td><td align="center">0</td></tr><tr><td align="left"><bold>Ramipril</bold></td><td align="center">−7.7464</td><td align="center">1.6166</td><td align="center">O-58</td><td align="center">N</td><td align="center">Ile 291</td><td align="center">H-acceptor</td><td align="center">3.47</td><td align="center">−0.8</td></tr><tr><td rowspan="7"><bold>Ramiprilat</bold></td><td rowspan="7">−6.9943</td><td rowspan="7" align="center">2.4607</td><td align="center">O-49</td><td align="center">Zn</td><td align="center">Zn 901</td><td rowspan="4" align="center">metallic</td><td align="center">2.01</td><td align="center">−3.9</td></tr><tr><td rowspan="6" align="center">Zn-901</td><td align="center">NE2</td><td align="center">His 374</td><td align="center">2.4</td><td align="center">−3.2</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td align="center">2.27</td><td align="center">−5.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−5.6</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td rowspan="3" align="center">ionic</td><td align="center">2.27</td><td align="center">−11.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−14.4</td></tr><tr><td align="center">OE2</td><td align="center">Glu 402</td><td align="center">3.13</td><td align="center">−3.7</td></tr></tbody></table></table-wrap><table-wrap id="t0006" orientation="portrait" position="float"><label>Table 6.</label><caption><p>The results obtained from docking of Drugs with <bold>6M0J</bold> in <bold>site
2</bold>.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col></colgroup><thead><tr><th rowspan="2" align="left">Drugs</th><th rowspan="2" align="center">S score
(kcal/mol)</th><th rowspan="2" align="center">RMSD (Å)</th><th colspan="6" align="center">Bonds
between atoms of compounds and residues of active site 2 of 6M0J<hr></hr></th></tr><tr><th align="center">Atom of compound</th><th align="center">Atom of receptor</th><th align="center">Involved receptor
residues</th><th align="center">Type of interaction
bond</th><th align="center">Distance (Å)</th><th align="center">E (kcal/mol)</th></tr></thead><tbody valign="top"><tr><td align="left"><bold>Chloroquine</bold></td><td align="center">−5.4920</td><td align="center">2.3627</td><td align="center">C-45</td><td align="center">5-ring</td><td align="center">His 401</td><td align="center">H-pi</td><td align="center">4.25</td><td align="center">−0.9</td></tr><tr><td rowspan="7"><bold>Delapril</bold></td><td rowspan="7" align="center"><bold>-8.1604</bold></td><td rowspan="7" align="center">1.5603</td><td align="center">O-26</td><td align="center">ZN</td><td align="center">Zn 901</td><td rowspan="4" align="center">metallic</td><td align="center">2.13</td><td align="center">−3.6</td></tr><tr><td rowspan="6" align="center">Zn-901</td><td rowspan="2" align="center">NE2</td><td align="center">His 374</td><td align="center">2.4</td><td align="center">−3.2</td></tr><tr><td align="center">His 378</td><td align="center">2.27</td><td align="center">−5.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−5.6</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td rowspan="3" align="center">ionic</td><td align="center">2.27</td><td align="center">−11.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−14.4</td></tr><tr><td align="center">OE2</td><td align="center">Glu 402</td><td align="center">3.13</td><td align="center">−3.7</td></tr><tr><td rowspan="8"><bold>Enalapril</bold></td><td rowspan="8">−6.7570</td><td rowspan="8" align="center">2.6763</td><td align="center">O-14</td><td align="center">ZN</td><td align="center">Zn 901</td><td rowspan="4" align="center">metallic</td><td align="center">2</td><td align="center">−2.5</td></tr><tr><td rowspan="6" align="center">Zn-901</td><td align="center">NE2</td><td align="center">His 374</td><td align="center">2.4</td><td align="center">−3.2</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td align="center">2.27</td><td align="center">−5.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−5.6</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td rowspan="3" align="center">ionic</td><td align="center">2.27</td><td align="center">−11.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−14.4</td></tr><tr><td align="center">OE2</td><td align="center">Glu 402</td><td align="center">3.13</td><td align="center">−3.7</td></tr><tr><td align="center">C-52</td><td align="center">5-ring</td><td align="center">His 378</td><td align="center">H-pi</td><td align="center">3.88</td><td align="center">−1</td></tr><tr><td rowspan="9"><bold>Hydroxychloroquine</bold></td><td rowspan="9">−6.3125</td><td rowspan="9" align="center">1.8513</td><td align="center">O-2</td><td align="center">OE2</td><td align="center">Glu 375</td><td align="center">H-donor</td><td align="center">2.86</td><td align="center">−1.9</td></tr><tr><td align="center">O-2</td><td align="center">ZN</td><td align="center">Zn 901</td><td rowspan="4" align="center">metallic</td><td align="center">2</td><td align="center">−2.6</td></tr><tr><td rowspan="6" align="center">Zn-901</td><td align="center">NE2</td><td align="center">His 374</td><td align="center">2.4</td><td align="center">−3.2</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td align="center">2.27</td><td align="center">−5.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−5.6</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td rowspan="3" align="center">ionic</td><td align="center">2.27</td><td align="center">−11.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−14.4</td></tr><tr><td align="center">OE2</td><td align="center">Glu 402</td><td align="center">3.13</td><td align="center">−3.7</td></tr><tr><td align="center">C-47</td><td align="center">5-ring</td><td align="center">His 378</td><td align="center">H-pi</td><td align="center">4.12</td><td align="center">−0.6</td></tr><tr><td rowspan="9"><bold>Lisinopril</bold></td><td rowspan="9">−6.6966</td><td rowspan="9" align="center">1.9981</td><td align="center">O-5</td><td align="center">O</td><td align="center">H<sub>2</sub>O 1004</td><td align="center">H-donor</td><td align="center">2.97</td><td align="center">−2</td></tr><tr><td align="center">O-1</td><td align="center">ZN</td><td align="center">Zn 901</td><td rowspan="4" align="center">metallic</td><td align="center">2.06</td><td align="center">−2.3</td></tr><tr><td rowspan="6" align="center">Zn-901</td><td align="center">NE2</td><td align="center">His 374</td><td align="center">2.4</td><td align="center">−3.2</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td align="center">2.27</td><td align="center">−5.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−5.6</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td rowspan="3" align="center">ionic</td><td align="center">2.27</td><td align="center">−11.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−14.4</td></tr><tr><td align="center">OE2</td><td align="center">Glu 402</td><td align="center">3.13</td><td align="center">−3.7</td></tr><tr><td align="center">6-ring</td><td align="center">N</td><td align="center">Ile 291</td><td align="center">pi-H</td><td align="center">3.98</td><td align="center">−1.1</td></tr><tr><td rowspan="9"><bold>ORE-1001</bold></td><td rowspan="9">−6.2755</td><td rowspan="9" align="center">2.5319</td><td align="center">N-6</td><td align="center">OH</td><td align="center">Tyr 515</td><td align="center">H-acceptor</td><td align="center">3.09</td><td align="center">−2.1</td></tr><tr><td align="center">O-25</td><td align="center">ZN</td><td align="center">Zn 901</td><td rowspan="5" align="center">metallic</td><td align="center">2.09</td><td align="center">−2.3</td></tr><tr><td align="center">O-31</td><td align="center">ZN</td><td align="center">Zn 901</td><td align="center">2.31</td><td align="center">−0.9</td></tr><tr><td rowspan="6" align="center">Zn-901</td><td align="center">NE2</td><td align="center">His 374</td><td align="center">2.4</td><td align="center">−3.2</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td align="center">2.27</td><td align="center">−5.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−5.6</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td rowspan="3" align="center">ionic</td><td align="center">2.27</td><td align="center">−11.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−14.4</td></tr><tr><td align="center">OE2</td><td align="center">Glu 402</td><td align="center">3.13</td><td align="center">−3.7</td></tr><tr><td rowspan="12"><bold>Perindopril</bold></td><td rowspan="12">−6.7968</td><td rowspan="12" align="center">2.2965</td><td align="center">O-23</td><td align="center">O</td><td align="center">Glu 398</td><td rowspan="3" align="center">H-donor</td><td align="center">2.84</td><td align="center">−3.1</td></tr><tr><td align="center">N-26</td><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">3.11</td><td align="center">−1.4</td></tr><tr><td align="center">C-46</td><td align="center">OE2</td><td align="center">Glu 375</td><td align="center">3.49</td><td align="center">−0.6</td></tr><tr><td align="center">O-16</td><td align="center">O</td><td align="center">H<sub>2</sub>O 1033</td><td rowspan="2" align="center">H-acceptor</td><td align="center">2.86</td><td align="center">−1.9</td></tr><tr><td align="center">O-25</td><td align="center">NH2</td><td align="center">Arg 514</td><td align="center">2.91</td><td align="center">−1.9</td></tr><tr><td align="center">O-42</td><td align="center">ZN</td><td align="center">Zn 901</td><td rowspan="4" align="center">metallic</td><td align="center">1.97</td><td align="center">−2.9</td></tr><tr><td rowspan="6" align="center">Zn-901</td><td align="center">NE2</td><td align="center">His 374</td><td align="center">2.4</td><td align="center">−3.2</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td align="center">2.27</td><td align="center">−5.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−5.6</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td rowspan="3" align="center">ionic</td><td align="center">2.27</td><td align="center">−11.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−14.4</td></tr><tr><td align="center">OE2</td><td align="center">Glu 402</td><td align="center">3.13</td><td align="center">−3.7</td></tr><tr><td rowspan="8"><bold>Ramipril</bold></td><td rowspan="8">−7.6305</td><td rowspan="8" align="center">2.4853</td><td align="center">O-53</td><td align="center">ZN</td><td align="center">Zn 901</td><td rowspan="5" align="center">metallic</td><td align="center">2.13</td><td align="center">−1.7</td></tr><tr><td align="center">O-58</td><td align="center">ZN</td><td align="center">Zn 901</td><td align="center">2.44</td><td align="center">−1.4</td></tr><tr><td rowspan="6" align="center">Zn-901</td><td align="center">NE2</td><td align="center">His 374</td><td align="center">2.4</td><td align="center">−3.2</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td align="center">2.27</td><td align="center">−5.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−5.6</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td rowspan="3" align="center">ionic</td><td align="center">2.27</td><td align="center">−11.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−14.4</td></tr><tr><td align="center">OE2</td><td align="center">Glu 402</td><td align="center">3.13</td><td align="center">−3.7</td></tr><tr><td rowspan="7"><bold>Ramiprilat</bold></td><td rowspan="7">−7.1864</td><td rowspan="7" align="center">1.7252</td><td align="center">O-45</td><td align="center">Zn</td><td align="center">Zn 901</td><td rowspan="4" align="center">metallic</td><td align="center">1.94</td><td align="center">−2.9</td></tr><tr><td rowspan="6" align="center">Zn-901</td><td align="center">NE2</td><td align="center">His 374</td><td align="center">2.4</td><td align="center">−3.2</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td align="center">2.27</td><td align="center">−5.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−5.6</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td rowspan="3" align="center">ionic</td><td align="center">2.27</td><td align="center">−11.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−14.4</td></tr><tr><td align="center">OE2</td><td align="center">Glu 402</td><td align="center">3.13</td><td align="center">−3.7</td></tr><tr><td rowspan="9"><bold>Trandolapril</bold></td><td rowspan="9">−7.1160</td><td rowspan="9" align="center">1.9818</td><td align="center">O-1</td><td align="center">O</td><td align="center">H<sub>2</sub>O 1030</td><td align="center">H-acceptor</td><td align="center">3.04</td><td align="center">−1</td></tr><tr><td align="center">O-4</td><td align="center">ZN</td><td align="center">Zn 901</td><td rowspan="4" align="center">metallic</td><td align="center">2.07</td><td align="center">−3.8</td></tr><tr><td rowspan="6" align="center">Zn-901</td><td align="center">NE2</td><td align="center">His 374</td><td align="center">2.4</td><td align="center">−3.2</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td align="center">2.27</td><td align="center">−5.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−5.6</td></tr><tr><td align="center">NE2</td><td align="center">His 378</td><td rowspan="3" align="center">ionic</td><td align="center">2.27</td><td align="center">−11.7</td></tr><tr><td align="center">OE1</td><td align="center">Glu 402</td><td align="center">2.1</td><td align="center">−14.4</td></tr><tr><td align="center">OE2</td><td align="center">Glu 402</td><td align="center">3.13</td><td align="center">−3.7</td></tr><tr><td align="center">6-ring</td><td align="center">CA</td><td align="center">Glu 398</td><td align="center">pi-H</td><td align="center">3.63</td><td align="center">−0.6</td></tr></tbody></table></table-wrap><p>The results of the binding of drugs with <bold>6M0J</bold> in site <bold>1</bold> are
shown in <xref ref-type="fig" rid="F0007">Figure 7</xref>. From the <xref ref-type="fig" rid="F0007">Figure 7</xref>, It is apparent that <bold>Piperaquine</bold> had pi-pi
interaction with amino acid Phe438, whereas <bold>Hydroxychloroquine</bold> had pi-H and
pi-pi interactions with amino acid Phe438 and <bold>Delapril</bold> had numerous
interactions; H-donor interaction with amino acid Glu375, H-acceptor with Arg514 and
metallic interaction with zinc.</p><fig id="F0007" orientation="portrait" position="float"><label>Figure 7.</label><caption><p>Compounds binding with <bold>6M0J</bold> in site <bold>1</bold>.</p></caption><graphic content-type="color" xlink:href="TBSD_A_1803967_F0007_C"></graphic></fig><p>The interaction of carboxylic functional group in <bold>Delapril</bold> with zinc
motivates the zinc to interact with His374 by metallic interaction and with His378 and
Glu402 by ionic and metallic interactions respectively. As mentioned above, zinc had an
antiviral activity and this type of interaction may inhibit the COVID-19.</p><p>The results of docking of drugs with <bold>6M0J</bold> in site <bold>2</bold> are shown
in <xref rid="t0006" ref-type="table">Table 6</xref>. According to the results in this
site 2, almost all drugs make interacted in pocket S2 via zinc. <bold>Delapril</bold>showed excellent docking score −8.1604 Kcal/mol and RMSD 1.5603 Å compared with
<bold>Perindopril</bold>, <bold>Lisinopril</bold>, <bold>Hydroxychloroquine</bold> and
<bold>Ramipril</bold> with energy scores and RMSD values of (-6.7968 kcal/mol,
2.2965 Å), (-6.6966 Kcal/mol, 1.9981 Å), (-6.3125 Kcal/mol, 1.8513 Å) and
(-7.6305 kcal/mol, 2.4853 Å) respectively.</p><p>Although in site 2, <bold>Enalaprilat</bold>, <bold><italic>N</italic>-(2-aminoethyl)-1-aziridineethamine</bold>, <bold>Piperaquine</bold>,
<bold>Piperazine</bold>, <bold>Quinacrine Mustard</bold>, <bold>Trandolaprilat</bold>and <bold>Quinacrine</bold> have interactions with the active site but they have
unacceptable RMSD values.</p><p>In all pockets, <bold><italic>N</italic>-(2-aminoethyl)-1-aziridineethamine</bold>,
<bold>Triethylenetetramine</bold> and <bold>Piperazine</bold> had energy docking
scores higher than −4 Kcal/mol, they had energy scores out of the accepted limit,
therefore these compounds could not be considered. Also, in all results,
<bold>Chloroquine</bold> had energy scores higher than <bold>Hydroxychloroquine</bold>and <bold>Delapril</bold>.</p><p><xref ref-type="fig" rid="F0008">Figure 8</xref> presents the interactions of drugs
with <bold>6M0J</bold> in site <bold>2</bold>. From <xref ref-type="fig" rid="F0008">Figure 8</xref>, it can be seen that <bold>Delapril</bold> had a metallic interaction
with Zn, meanwhile Zn interacts with three amino acids by two types of interactions.
These are: two ionic and one metallic interactions with Glu402, one ionic and one
metallic interactions with His378 and ionic interaction with His374.</p><fig id="F0008" orientation="portrait" position="float"><label>Figure 8.</label><caption><p>Compounds binding with <bold>6M0J</bold> in site <bold>2</bold>.</p></caption><graphic content-type="color" xlink:href="TBSD_A_1803967_F0008_C"></graphic></fig><p><bold>Perindopril</bold> had many interactions, three H-donor interactions with amino
acids Glu398, Glu402 and Glu375, two H-acceptor with water and with amino acid Arg514 as
well as metallic interaction with Zn. Meanwhile Zn had two ionic and metallic
interactions, with amino acid Glu402, metallic and ionic interactions with amino acid
His378 and metallic interaction with amino acid His374.</p><p><bold>Hydroxychloroquine</bold> had H-donor interaction with amino acid Glu375,
metallic interaction with Zn, H-pi interaction with amino acid His378, while Zn had the
same interactions with these amino acids. <bold>Lisinopril</bold> had H-donor
interaction with water and metallic interaction with Zn, whereas Zn interacts with the
same amino acids. <bold>Ramipril</bold> had two metallic interaction with Zn. whereas Zn
interacts with the same amino acids.</p></sec></sec><sec id="S0006-S2002" disp-level="2"><label>6.2.</label><title>Global reactivity descriptors</title><p>The chemical reactivity descriptors were calculated and presented in <xref rid="t0007" ref-type="table">Table 7</xref>. The E<sub>HOMO</sub> and E<sub>LUMO</sub>were obtained from GaussView (Dennington et al., <xref rid="CIT0015" ref-type="bibr">2016</xref>). The results of the global hardness and softness, which they are related
to the stability of chemical system, as shown in <xref rid="t0007" ref-type="table">Table
7</xref>, indicate that <bold>Ramipril</bold>, <bold>Chloroquine</bold>,
<bold>ORE-1001</bold> and <bold>Delapril</bold> are harder than the
<bold>Hydroxychloroquine</bold> and other compounds.</p><table-wrap id="t0007" orientation="portrait" position="float"><label>Table 7.</label><caption><p>HOMO and LUMO energy, energy gap ΔE and global reactivity indices µ, ω, η and N for
drugs.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col></colgroup><thead><tr><th align="left">Drugs</th><th align="center">HOMO (eV)</th><th align="center">LUMO (eV)</th><th align="center">ΔE (eV)</th><th align="center">η (eV)</th><th align="center">S (eV)</th><th align="center">µ (eV)</th><th align="center">ω (eV)</th><th align="center">N (eV)</th></tr></thead><tbody valign="top"><tr><td align="left"><bold>Chloroquine</bold></td><td align="center">−5.4861</td><td align="center">−1.2232</td><td align="center">4.2629</td><td align="center">2.1315</td><td align="center">173.6972</td><td align="center">−3.3546</td><td align="center">2.6398</td><td align="center">3.1698</td></tr><tr><td align="left"><bold>Delapril</bold></td><td align="center">−5.9438</td><td align="center">−0.5853</td><td align="center">5.3585</td><td align="center">2.6792</td><td align="center">138.1850</td><td align="center">−3.2646</td><td align="center">1.9888</td><td align="center">2.7121</td></tr><tr><td align="left"><bold>Enalapril</bold></td><td align="center">−5.7435</td><td align="center">−0.7380</td><td align="center">5.0055</td><td align="center">2.5028</td><td align="center">147.9282</td><td align="center">−3.2407</td><td align="center">2.0981</td><td align="center">2.9124</td></tr><tr><td align="left"><bold>Hydroxychloroquine</bold></td><td align="center">−6.5095</td><td align="center">0.2797</td><td align="center">6.7892</td><td align="center">3.3946</td><td align="center">109.0637</td><td align="center">−3.1149</td><td align="center">1.4291</td><td align="center">2.1464</td></tr><tr><td align="left"><bold>Lisinopril</bold></td><td align="center">−6.6328</td><td align="center">−1.0583</td><td align="center">5.5745</td><td align="center">2.7873</td><td align="center">132.8292</td><td align="center">−3.8455</td><td align="center">2.6527</td><td align="center">2.0231</td></tr><tr><td align="left"><bold>ORE-1001</bold></td><td align="center">−6.9346</td><td align="center">−1.9323</td><td align="center">5.0023</td><td align="center">2.5011</td><td align="center">148.0248</td><td align="center">−4.4334</td><td align="center">3.9292</td><td align="center">1.7213</td></tr><tr><td align="left"><bold>Perindopril</bold></td><td align="center">−5.6564</td><td align="center">0.3793</td><td align="center">6.0358</td><td align="center">3.0179</td><td align="center">122.6789</td><td align="center">−2.6386</td><td align="center">1.1534</td><td align="center">2.9995</td></tr><tr><td align="left"><bold>Piperaquine</bold></td><td align="center">−6.9269</td><td align="center">0.0678</td><td align="center">6.9947</td><td align="center">3.4973</td><td align="center">105.8603</td><td align="center">−3.4296</td><td align="center">1.6815</td><td align="center">1.7290</td></tr><tr><td align="left"><bold>Ramipril</bold></td><td align="center">−6.0807</td><td align="center">−3.1299</td><td align="center">2.9508</td><td align="center">1.4754</td><td align="center">250.9350</td><td align="center">−4.6053</td><td align="center">7.1873</td><td align="center">2.5752</td></tr><tr><td align="left"><bold>Ramiprilat</bold></td><td align="center">−6.4178</td><td align="center">−0.3420</td><td align="center">6.0758</td><td align="center">3.0379</td><td align="center">121.8712</td><td align="center">−3.3799</td><td align="center">1.8802</td><td align="center">2.2381</td></tr><tr><td align="left"><bold>Trandolapril</bold></td><td align="center">−6.1084</td><td align="center">−0.7565</td><td align="center">5.3519</td><td align="center">2.6760</td><td align="center">138.3537</td><td align="center">−3.4324</td><td align="center">2.2013</td><td align="center">2.5475</td></tr></tbody></table><table-wrap-foot><fn id="TF1"><p><bold>Notes:</bold> the HOMO energy -8.6559 eV. of the reference system (TCE) had
been calculated at DFT/B3LYP 6-31 G.</p></fn></table-wrap-foot></table-wrap><p>In addition, <bold>Ramipril</bold> have the smaller energy gap (Δ<italic>E</italic> = 2.9508 eV), <bold>Delapril</bold> and <bold>Lisinopril</bold> have smaller
energy gaps than <bold>Hydroxychloroquine</bold>. Moreover, <bold>Ramipril</bold>,
<bold>Chloroquine</bold>, <bold>ORE-1001</bold> and <bold>Delapril</bold> have softness
values higher than that of <bold>Hydroxychloroquine</bold>. These results indicate that
<bold>Ramipril</bold>, <bold>Chloroquine</bold>, <bold>ORE-1001</bold> and
<bold>Delapril</bold> are more stable and more reactive than
<bold>Hydroxychloroquine</bold>.</p><p>The electronic chemical potential (µ) for <bold>Perindopril</bold> (µ= −2.6386 eV) is
higher than other compounds followed by <bold>Hydroxychloroquine</bold>,
<bold>Enalapril</bold> and <bold>Delapril</bold>. According to these results, these
compounds can exchange electron density with the environment efficiently (Azarhazin
et al., <xref rid="CIT0004" ref-type="bibr">2019</xref>).</p><p>A further classification of organic molecules as strong (<italic>N</italic> > 3 eV), moderate (2.0 eV ≤ <italic>N</italic> ≤ 3.0 eV) and
marginal nucleophilic (<italic>N</italic> < 2.0 eV) were obtained by
analysis of a series of common nucleophilic species participating in polar organic
reaction. Note that nucleophilicity value is referred to tetracyanoethylen (TCE) taken as
a reference, because it presents the lowest E<sub>HOMO</sub> in a large series of molecule
already investigated (Jaramillo et al., <xref rid="CIT0027" ref-type="bibr">2008</xref>).
According to the results in <xref rid="t0007" ref-type="table">Table 7</xref>,
<bold>Chloroquine</bold> can be classified as strong nucleophile and the others as
moderate nucleophile except <bold>ORE-1001</bold>, which is considered as marginal
nucleophile.</p><table-wrap id="t0008" orientation="portrait" position="float"><label>Table 8.</label><caption><p>Calculated MM-GBSA binding energies (in kcal/mol) for the Delapril, Lisinopril and
Ramipril drugs against <bold>6M0J</bold> over MD simulations.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="1*"></col><col width="1*"></col><col width="1*"></col></colgroup><thead><tr><th align="left">Drugs</th><th align="center">Site 1</th><th align="center">Site 2</th></tr></thead><tbody valign="top"><tr><td align="left"><bold>Delapril</bold></td><td align="left">−54</td><td align="left">−45</td></tr><tr><td align="left"><bold>Lisinopril</bold></td><td align="left">−33</td><td align="left">−38</td></tr><tr><td align="left"><bold>Ramipril</bold></td><td align="left">−46</td><td align="left">−42</td></tr></tbody></table></table-wrap><p>The electrophilicity ω had become a potent tool for the study of the reactivity of
organic compounds that can participate in polar reaction (Domingo et al., <xref rid="CIT0017" ref-type="bibr">2016</xref>; Srivastava, <xref rid="CIT0044" ref-type="bibr">2020</xref>). <bold>Ramipril</bold> had the highest electrophilicity value
(ω = 7.1873 eV), whereas as <bold>Delapril</bold> had an electrophilicity value
(ω = 1.9888 eV) higher more than that of <bold>Hydroxychloroquine</bold>(ω = 1.4291 eV).</p></sec><sec id="S0006-S2003" disp-level="2"><label>6.3.</label><title>Molecular dynamics simulation</title><p>In order to examine the conformational flexibilities of docked drug-receptor complexes
and to attain dependable drug-receptor–binding affinities, the MD process combined with
binding energy (MM-GBSA) (De Vivo et al., <xref rid="CIT0013" ref-type="bibr">2016</xref>;
Kerrigan, <xref rid="CIT0029" ref-type="bibr">2013</xref>)calculations was run for 600 ps
on the most promising drugs <bold>Delapril</bold>, <bold>Lisinopril</bold> and
<bold>Ramipril</bold> to target [SARS-CoV-2/ACE2] complex (<bold>6M0J</bold>). The
evaluated average MM-GBSA binding energies are given in <xref rid="t0008" ref-type="table">Table 8</xref>.</p><p>In general, it is apparent from this table that the selected three drugs exhibited
considerable binding energies). In site 2, <bold>Delapril</bold> and <bold>Ramipril</bold>showed promising binding energies −54 and −46 kcal/mol respectively. On the other hand,
<bold>Lisinopril</bold> showed relatively weak binding energy −33 kcal/mol. Whereas, in
site 2, all three drugs <bold>Delapril</bold>, <bold>Lisinopril</bold> and
<bold>Ramipril</bold> showed promising binding affinities with binding energies.</p><p><xref ref-type="fig" rid="F0009">Figures 9</xref> and <xref ref-type="fig" rid="F0010">10</xref> show the results of the atomic potential energy function during dynamic study
calculation for <bold>Delapril, Lisinopril</bold> and <bold>Ramipril</bold> in the
<bold>6M0J</bold> at site 1 and 2 respectively. To explore the dynamic stability of the
6M0J/inhibitor drugs complexes, the time-dependent potential energy of the complex were
calculated during MD trajectories. It is apparent in <xref ref-type="fig" rid="F0009">Figure 9</xref>, <bold>site 1</bold>, that complex A <bold>(6M0J/Delapril)</bold>achieved equilibrium around 300 ps. Meanwhile complex B <bold>(6M0J/Lisinopril)</bold>achieved the equilibrium around 350 ps. Whereas, complex C <bold>(6M0J/Ramipril)</bold>achieved the equilibrium stability around 400 ps. It can be seen from <xref ref-type="fig" rid="F0010">Figure 10</xref>, <bold>site 2,</bold> that the complex A achieved the
equilibrium stability around 400 ps, complex B achieve the equilibrium stability around
400 ps, meanwhile complex C achieve the equilibrium stability around 350 ps.</p><fig id="F0009" orientation="portrait" position="float"><label>Figure 9.</label><caption><p>The evaluation of potential energy of complex of (A) <bold>Delapril</bold>, (B)
<bold>Lisinopril</bold> and (C) <bold>Ramipril</bold> with <bold>6M0J</bold>receptor site <bold>1</bold> as function of time.</p></caption><graphic content-type="color" xlink:href="TBSD_A_1803967_F0009_C"></graphic></fig><fig id="F0010" orientation="portrait" position="float"><label>Figure 10.</label><caption><p>The evaluation of potential energy of complex of (A) <bold>Delapril</bold>, (B)
<bold>Lisinopril</bold> and (C) <bold>Ramipril</bold> with <bold>6M0J</bold>receptor site <bold>2</bold> as function of time.</p></caption><graphic content-type="color" xlink:href="TBSD_A_1803967_F0010_C"></graphic></fig><p>In general, if the interaction energy between a residue and a ligand is lower than
−0.8 Kcal/mol, the residue is regarded as an important residue in the molecular
recognition of the ligand. For the 6M0J/Delapril complex A (<xref ref-type="fig" rid="F0011">Figure 11</xref>), the major favourable energy contributions (-2.2 to
−1.4 kcal/mol) originate predominately from Glu375 (-1.4), H<sub>2</sub>O1030 (-1.5) and
Trp203 (-2.2), As shown in <xref ref-type="fig" rid="F0011">Figure 11</xref> the complex B
had energy binding with Asp292 (-7.8) and Ala413 (-4.7). However, complex C did not
interact in this site.</p><fig id="F0011" orientation="portrait" position="float"><label>Figure 11.</label><caption><p>Docked pose and binding interaction of (A) <bold>Delapril</bold>, (B)
<bold>Lisinopril</bold>, (C) <bold>Ramipril</bold> with <bold>6M0J</bold> in site
<bold>1</bold>.</p></caption><graphic content-type="color" xlink:href="TBSD_A_1803967_F0011_C"></graphic></fig><p>It is clear from <xref ref-type="fig" rid="F0012">Figure. 12</xref> that complex A had
interactions in site 2 of <bold>6M0J</bold> with Glu375 (-8.7) and Zn901 (-3.4), while
complex B had the major favourable energy contributions (-0.6 to −6.2 kcal/mol) which
originate predominately from Glu402 (-2.3), Asp382 (-6.2), H<sub>2</sub>O1033 (-1.3),
Tyr510 (-2.8), H<sub>2</sub>O1004 (-1.5), His401 (-0.6) and Trp349 (-1). Nevertheless,
His401 cannot be considered as an important residue.</p><fig id="F0012" orientation="portrait" position="float"><label>Figure 12.</label><caption><p>Docked pose and binding interaction of (A) <bold>Delapril</bold>, (B)
<bold>Lisinopril</bold>, (C) <bold>Ramipril</bold> with <bold>6M0J</bold> in site
<bold>2</bold>.</p></caption><graphic content-type="color" xlink:href="TBSD_A_1803967_F0012_C"></graphic></fig><p>Complex C showed more favourable interactions with residues Glu402 (-3.8),
H<sub>2</sub>O1030 (-1.3), H<sub>2</sub>O1002 (-0.9), Zn901 (-4.1) and Asp350 (-2).</p></sec></sec><sec id="S0007" disp-level="1"><label>7.</label><title>Conclusion</title><p>The aim of the present research was to examine the binding of eighteen candidate drugs with
ACE2 enzyme and [SARS-CoV-2/ACE2] complex using docking analysis. The docking ranking
results in this study showed that some of these ligands might have the ability to inhibit
SARS-CoV-2. The results of docking these ligands with ACE2 enzyme (1R42) in two pockets
indicated that <bold>Delapril</bold> gave the lowest energy score and good RMSD value
followed by <bold>Lisinopril</bold> (site1) and <bold>Ramipril</bold> (site 2). In addition,
the docking results with 6M0J showed that only <bold>Delapril</bold> and
<bold>Ramiprilat</bold> interacted with <bold>Zn</bold> in site 1, while in site 2
<bold>Delapril</bold> gave the best energy score followed by <bold>Ramipril</bold>. The
drugs mentioned above presented good results with the two chosen enzymes compared with
<bold>Chloroquine</bold> and <bold>Hydroxychloroquine</bold>. Moreover, the results
obtained from global reactivity indices indicated that <bold>Ramipril</bold> is the most
reactive drug, it had the highest electrophilicity value followed by <bold>ORE-1001</bold>,
<bold>Chloroquine</bold> and <bold>Lisinopril</bold>. The most obvious finding to emerge
from this study is that <bold>Ramipril</bold>, <bold>Delapril</bold> and
<bold>Lisinopril</bold> gave good docking results compared with <bold>Chloroquine</bold>and <bold>Hydroxychloroquine</bold>. Also, <bold>Delapril</bold>, <bold>Lisinopril</bold>and <bold>Ramipril</bold> showed encouraging binding affinity, MM/GBSA energies, to
[SARS-CoV-2/ACE2] complex. Further investigation and experimentation into
<bold>Delapril</bold>, <bold>Lisinopril</bold> and <bold>Ramipril</bold>, which they are
promising candidate drugs for COVID-19 patients, is strongly recommended.</p></sec></body><back><sec id="S0008" disp-level="1" sec-type="COI-statement"><title>Disclosure statement</title><p>No potential conflict of interest was reported by the authors.</p></sec><ref-list><title>References</title><ref id="CIT0001"><mixed-citation publication-type="journal"><person-group person-group-type="author"><string-name><surname>Adeoye</surname>, <given-names>A.
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