High-throughput virtual screening and docking studies of matrix protein vp40 of ebola virus
Identifieur interne : 000823 ( Pmc/Corpus ); précédent : 000822; suivant : 000824High-throughput virtual screening and docking studies of matrix protein vp40 of ebola virus
Auteurs : Thangaraju Tamilvanan ; Waheeta HopperSource :
- Bioinformation [ 0973-8894 ] ; 2013.
Abstract
Url:
DOI: 10.6026/97320630009286
PubMed: 23559747
PubMed Central: 3607187
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PMC:3607187Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">High-throughput virtual screening and docking studies of matrix protein vp40 of ebola virus</title><author><name sortKey="Tamilvanan, Thangaraju" sort="Tamilvanan, Thangaraju" uniqKey="Tamilvanan T" first="Thangaraju" last="Tamilvanan">Thangaraju Tamilvanan</name></author><author><name sortKey="Hopper, Waheeta" sort="Hopper, Waheeta" uniqKey="Hopper W" first="Waheeta" last="Hopper">Waheeta Hopper</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23559747</idno><idno type="pmc">3607187</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607187</idno><idno type="RBID">PMC:3607187</idno><idno type="doi">10.6026/97320630009286</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000823</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000823</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">High-throughput virtual screening and docking studies of matrix protein vp40 of ebola virus</title><author><name sortKey="Tamilvanan, Thangaraju" sort="Tamilvanan, Thangaraju" uniqKey="Tamilvanan T" first="Thangaraju" last="Tamilvanan">Thangaraju Tamilvanan</name></author><author><name sortKey="Hopper, Waheeta" sort="Hopper, Waheeta" uniqKey="Hopper W" first="Waheeta" last="Hopper">Waheeta Hopper</name></author></analytic><series><title level="j">Bioinformation</title><idno type="ISSN">0973-8894</idno><idno type="eISSN">0973-2063</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><italic>Ebolavirus</italic>, a member of the <italic>Filoviridae</italic> family of negative-sense RNA viruses, causes severe haemorrhagic fever leading up to 90%
lethality. <italic>Ebolavirus</italic> matrix protein VP40 is involved in the virus assembly and budding process. The RNA binding pocket of VP40
is considered as the drug target site for structure based drug design. High Throughput Virtual Screening and molecular docking
studies were employed to find the suitable inhibitors against VP40. Ten compounds showing good glide score and glide energy as
well as interaction with specific amino acid residues were short listed as drug leads. These small molecule inhibitors could be
potent inhibitors for VP40 matrix protein by blocking virus assembly and budding process.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Borio, L" uniqKey="Borio L">L Borio</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bray, M" uniqKey="Bray M">M Bray</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Atlas, Rm" uniqKey="Atlas R">RM Atlas</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Adrian, M" uniqKey="Adrian M">M Adrian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Towner, Js" uniqKey="Towner J">JS Towner</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Sullivan, Nj" uniqKey="Sullivan N">NJ Sullivan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hevey, M" uniqKey="Hevey M">M Hevey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rao, M" uniqKey="Rao M">M Rao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Riemenschneider, J" uniqKey="Riemenschneider J">J Riemenschneider</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mellquist Riemenschneider, Jl" uniqKey="Mellquist Riemenschneider J">JL Mellquist-Riemenschneider</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jones, Sm" uniqKey="Jones S">SM Jones</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, D" uniqKey="Wang D">D Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, D" uniqKey="Wang D">D Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Swenson, Dl" uniqKey="Swenson D">DL Swenson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Warfield, Kl" uniqKey="Warfield K">KL Warfield</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Swenson, Dl" uniqKey="Swenson D">DL Swenson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hevey, M" uniqKey="Hevey M">M Hevey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wilson, Ja" uniqKey="Wilson J">JA Wilson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Geisbert, Tw" uniqKey="Geisbert T">TW Geisbert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bavari, S" uniqKey="Bavari S">S Bavari</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gomis Ruth, Fx" uniqKey="Gomis Ruth F">FX Gomis-Rüth </name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ruigrok, Rw" uniqKey="Ruigrok R">RW Ruigrok</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Timmins, J" uniqKey="Timmins J">J Timmins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kaptur, Pe" uniqKey="Kaptur P">PE Kaptur</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Coronel, Ec" uniqKey="Coronel E">EC Coronel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stricker, R" uniqKey="Stricker R">R Stricker</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schmitt, Ap" uniqKey="Schmitt A">AP Schmitt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dessen, A" uniqKey="Dessen A">A Dessen</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Berman, Hm" uniqKey="Berman H">HM Berman</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Lipinski, Ca" uniqKey="Lipinski C">CA Lipinski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Laskowski, Ra" uniqKey="Laskowski R">RA Laskowski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Narayanan, K" uniqKey="Narayanan K">K Narayanan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ahmed, M" uniqKey="Ahmed M">M Ahmed</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Von, Kc" uniqKey="Von K">KC Von</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Harty, Rn" uniqKey="Harty R">RN Harty</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Timmins, J" uniqKey="Timmins J">J Timmins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Martin Serrano, J" uniqKey="Martin Serrano J">J Martin-Serrano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arthur, Jg" uniqKey="Arthur J">JG Arthur</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Aman, Mj" uniqKey="Aman M">MJ Aman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mike, Cw" uniqKey="Mike C">CW Mike</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jahrling, Pb" uniqKey="Jahrling P">PB Jahrling</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barrientos, Lg" uniqKey="Barrientos L">LG Barrientos</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Bioinformation</journal-id><journal-id journal-id-type="iso-abbrev">Bioinformation</journal-id><journal-id journal-id-type="publisher-id">Bioinformation</journal-id><journal-title-group><journal-title>Bioinformation</journal-title></journal-title-group><issn pub-type="ppub">0973-8894</issn><issn pub-type="epub">0973-2063</issn><publisher><publisher-name>Biomedical Informatics</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23559747</article-id><article-id pub-id-type="pmc">3607187</article-id><article-id pub-id-type="publisher-id">97320630009286</article-id><article-id pub-id-type="doi">10.6026/97320630009286</article-id><article-categories><subj-group subj-group-type="heading"><subject>Hypothesis</subject></subj-group></article-categories><title-group><article-title>High-throughput virtual screening and docking studies of matrix protein vp40 of ebola virus</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Tamilvanan</surname><given-names>Thangaraju</given-names></name></contrib><contrib contrib-type="author"><name><surname>Hopper</surname><given-names>Waheeta</given-names></name><xref ref-type="corresp" rid="COR1">*</xref></contrib><aff>Department of Bioinformatics, School of Bioengineering, Faculty of Engineering & Technology, SRM University, Kattankulathur, 603203, Tamil Nadu, India</aff></contrib-group><author-notes><corresp id="COR1"><label>*</label>Waheeta Hopper: <email>srmbioinforesearch@gmail.com</email> Phone: +91-44-27417813; Fax: +91-44-27452343</corresp></author-notes><pub-date pub-type="collection"><year>2013</year></pub-date><pub-date pub-type="epub"><day>19</day><month>3</month><year>2013</year></pub-date><volume>9</volume><issue>6</issue><fpage>286</fpage><lpage>292</lpage><history><date date-type="received"><day>19</day><month>2</month><year>2013</year></date><date date-type="accepted"><day>23</day><month>2</month><year>2013</year></date></history><permissions><copyright-statement>© 2013 Biomedical Informatics</copyright-statement><copyright-year>2013</copyright-year><license license-type="open-access"><license-p>This is an open-access article, which permits unrestricted use, distribution, and reproduction in any medium,
for non-commercial purposes, provided the original author and source are credited.</license-p></license></permissions><abstract><p><italic>Ebolavirus</italic>, a member of the <italic>Filoviridae</italic> family of negative-sense RNA viruses, causes severe haemorrhagic fever leading up to 90%
lethality. <italic>Ebolavirus</italic> matrix protein VP40 is involved in the virus assembly and budding process. The RNA binding pocket of VP40
is considered as the drug target site for structure based drug design. High Throughput Virtual Screening and molecular docking
studies were employed to find the suitable inhibitors against VP40. Ten compounds showing good glide score and glide energy as
well as interaction with specific amino acid residues were short listed as drug leads. These small molecule inhibitors could be
potent inhibitors for VP40 matrix protein by blocking virus assembly and budding process.</p></abstract><kwd-group><kwd><italic>Ebolavirus</italic></kwd><kwd>VP40</kwd><kwd>High throughput virtual screening</kwd><kwd>Molecular docking</kwd></kwd-group></article-meta></front><body><sec id="s1"><title>Background</title><p>The increased threat of terrorism necessitates an evaluation of
the risk posed by various microorganisms as biological
weapons. Especially, Filoviruses is one of such important
microorganisms. <italic>Ebola</italic> virus and <italic>Marburg</italic> virus are category A
bioweapon organisms. Biowarfare agents are considered as
potential biological weapons because they pose a threat as
lethal pathogens and because their use by terrorists might result
in extreme fear and panic [<xref ref-type="bibr" rid="R01">1</xref>,
<xref ref-type="bibr" rid="R02">2</xref>].</p><p>The attraction for bioweapons in war and for use in terroristic
attacks is attributed to their low production costs, the easy
access to a wide range of disease-producing biological agents,
their non-detection by routine security systems and their easy
transportation from one location to another [<xref ref-type="bibr" rid="R03">3</xref>]. Biological
weapons pose the most significant terrorism threat. They are
relatively easy to produce and could result in deaths
comparable to nuclear weapons [<xref ref-type="bibr" rid="R04">4</xref>].</p><p>Ebola hemorrhagic fever is an acute viral syndrome that leads
to fever and an ensuing bleeding diathesis that is marked by
high mortality in human and nonhuman primates. It is caused
by <italic>Ebola</italic> virus, a lipid-enveloped, negative strand RNA virus
that belongs to the viral family Filoviridae [<xref ref-type="bibr" rid="R05">5</xref>]. Case fatalities
range historically between 53 and 90% [<xref ref-type="bibr" rid="R06">6</xref>].</p><p><italic>Ebola</italic> virus infection in human causes severe disease for which
there is presently no vaccine or other treatment [<xref ref-type="bibr" rid="R07">7</xref>]. Vaccination
strategies based on single or multiple filovirus proteins have
examined the protective capacity of Glycoprotein (GP) alone
[<xref ref-type="bibr" rid="R08">8</xref>–<xref ref-type="bibr" rid="R15">15</xref>]
or in association with Nucleoprotein (NP) or Viral protein
(VP) [<xref ref-type="bibr" rid="R16">16</xref>–<xref ref-type="bibr" rid="R18">18</xref>].
The vaccine potential of other internal structural
proteins has been investigated as well. VP24, VP30, and VP35,
expressed by using recombinant venezuelan equine encephalitis
vectors, elicit some immunological response in rodents, but no
single VP could confer complete defence against lethal <italic>Ebola</italic>virus and <italic>Marburg</italic> virus challenges [<xref ref-type="bibr" rid="R19">19</xref>,
<xref ref-type="bibr" rid="R20">20</xref>].</p><p>VP40 plays an important role in virus assembly and budding,
VP40 is the most abundant protein in viral particles; it is located
under the viral bilayer to make structural integrity of the
particles. VP40 matrix protein assembles and budding process
take place at the plasma membrane, which requires lipid raft
micro domains [<xref ref-type="bibr" rid="R21">21</xref>,
<xref ref-type="bibr" rid="R22">22</xref>]. VP40 is active not only in the lipid
bilayer during the assembly process but also plays an important
role either in viral or host cell RNA metabolism during its
replication [<xref ref-type="bibr" rid="R23">23</xref>]. C-terminal domain of VP40 is required for
membrane association [<xref ref-type="bibr" rid="R24">24</xref>,
<xref ref-type="bibr" rid="R25">25</xref>].</p><p>Crystal structure of VP40 is an octamer, forms a pore-like
structure and binding with RNA. The protein-RNA interface is
stabilized by 140 amino acids residues of VP40 (including
Thr123, Phe125 and Arg134 amino acid residues of a fragment
of N-terminal domain) and UGA of RNA. The monomeric
structure having two domains, N-terminal and C-terminal
domains are involved in membrane association. RNA binding
pocket could serve as a target for antiviral drug development
[<xref ref-type="bibr" rid="R23">23</xref>].</p><p>Matrix protein and Ribonucleoprotein (RNP) interactions have
been reported for a number of enveloped viruses
[<xref ref-type="bibr" rid="R26">26</xref>–<xref ref-type="bibr" rid="R29">29</xref>]. Matrix
protein interacts with RNA in Thr123, Phe125 and Arg134
residues; these are the most important residues close to the
interface of the N- and C-terminal domains in the monomeric
conformation; which might implicate them in the transition
process. VP40 octameric structure shows that the interfaces of
the dimeric subunit are similar to the interface occupied by the
N-and C-terminal domains in the closed conformation
[<xref ref-type="bibr" rid="R30">30</xref>]. The
aim of this study was to identify potential lead compounds
against VP40 protein target using high throughput virtual
screening and molecular docking approaches and subjecting the
identified molecules for ADME analysis.</p></sec><sec sec-type="methods" id="s2"><title>Methodology</title><p>All the computational analysis were carried out using
Schrodinger suite version 9 [<xref ref-type="bibr" rid="R31">31</xref>]. Distance measuring and image
capturing were carried out using PyMol viewer version 1.3
[<xref ref-type="bibr" rid="R32">32</xref>].</p><sec id="s2a"><title><italic>Protein structure</italic>:</title><p>X-ray crystal structure of the matrix protein VP40 at 1.6 Å
resolution was retrieved from Protein Data Bank (PDB ID:
1H2C) [<xref ref-type="bibr" rid="R33">33</xref>]. Protein preparation wizard was used in
Schrodinger 2010. All the water molecules and RNA were
removed from the original crystal structure before protein
preparation process, to analyse the structure and the bond
order assigned, hydrogen atoms were added and the geometry
of all the hetero groups were corrected. Hydrogen bonds
assignment tool was used to optimize the hydrogen bond
network. Finally, impref optimized the position of hydrogen
bonds and keeping all the atoms in place. Energy minimization
was carried out using default constraint of the 0.3 Å of RMSD
and the OPLS_2005 force field.</p></sec><sec id="s2b"><title><italic>Receptor grid preparation</italic>:</title><p>Grids were generated by Receptor Grid Generation panel which
defines receptor structure by excluding any other cocrystallized
ligand that may be present, settle on the position
and size of the active site was represented by receptor grids.
Grid point's level for x, y, z axis (3.68, 19.15, 25.87) with in the
grid parameters Thr123, Phe125 & Arg134 amino acid residues
were present and grid generation was performed using
OPLS_2005.</p></sec><sec id="s2c"><title><italic>Compound database</italic>:</title><p>Traditional Chinese medicine (TCM) database contains more
than one lakh of compounds and Asinex database contains
202122 structures, assembled from the collection of 1115000
Asinex platinum compounds. Single low energy conformation
is stored for each of the 202122 database entries. 3D database
entries were created following AsinexDB_Pt_flex,
AsinexDB_flex and AsinexDB - Lipinski-filtered were cleaned
using LigPrep, with expansion of stereo centers whose chirality
was unspecified. This small molecules collection contains a high
percentage of drug like compounds [<xref ref-type="bibr" rid="R34">34</xref>,
<xref ref-type="bibr" rid="R35">35</xref>].</p></sec><sec id="s2d"><title><italic>High throughput virtual screening</italic>:</title><p>Virtual screening is the easiest method to identify and rank
potential drug candidates from a database of compounds.
Based on the active site of VP40, high throughput virtual
screening was performed using the Traditional Chinese
medicine and Asinex compound database. The compounds
were subjected to Glide based three-tiered docking strategy in
which all the compounds were docked by three stages of the
docking protocol, High Throughput Virtual Screening (HTVS),
Standard Precision (SP) and Extra precision (XP). First stage of
HTVS docking screens the ligands that are retrieved and all the
screened compounds are passed on to the second stage of SP
docking. The SP resultant compounds were then docked using
more accurate and computationally intensive XP mode. Based
on the glide score and glide energy, the protocol gives the leads
in XP descriptor. Glide module of the XP visualizer analyses the
specific interactions. Glide includes ligand-protein interaction
energies, hydrophobic interactions, hydrogen bonds, internal
energy, π-π stacking interactions and root mean square
deviation (RMSD) and desolvation.</p></sec><sec id="s2e"><title><italic>ADME screening</italic>:</title><p>ADME properties were calculated using molsoft [<xref ref-type="bibr" rid="R36">36</xref>]. Molsoft
predicts two properties, physically significant and
pharmaceutically relevant descriptors. Molsoft program will
predict the properties of the molecules, with a detailed analysis
of principal descriptors and physiochemical properties. It also
evaluates the acceptability of the analogues based on Lipinski's
rule of 5 [<xref ref-type="bibr" rid="R37">37</xref>], which are essential for drug-like pharmacokinetic
profile while using rational drug design.</p></sec></sec><sec id="s3"><title>Results & Discussion</title><p>The interaction between VP40 and RNA taken from PDBsum
[<xref ref-type="bibr" rid="R38">38</xref>] is shown in
(<xref ref-type="fig" rid="F1">Figure 1</xref>), about 4Å encircled around the
ligand (RNA) was considered for screening. The RNA
interaction stabilizes the octameric structure, RNA acts solely as
an adaptor in order to generate a confirmation of VP40 suitable
to interact with an unknown regulatory protein, active in the
virus life cycle. The octameric structure of VP40 provides the
frame work for a precise functional analysis, additionally RNA
presence of octameric structure VP40 infecting cells of RNA
binding pocket is a new target for antiviral drug development.
It has been learnt that there are three residues which are
essential for RNA binding namely; Thr123, Phe125, Arg134.
Three different levels of docking and scoring processes were
used for this study starting with HTVS, followed by SP and
finally with XP. VP40 protein target was docked with ASINEX
and TCM database using Glide. HTVS selected 16,747
compounds based on Glide score. SP docking filtered by
another Glide score criteria value (Glide score < -4.0 Kcal/mol)
which led to 249 ligands. The final docking with XP ranked the
249 best-scored compounds and ten compounds were selected
based on the Glide score. The ID's and H-Bond interactions of
the top ten scored compounds are shown in (<xref ref-type="fig" rid="F2">Figure 2</xref>).</p><p>Docking results showed that ASN03576800, ASN06396768,
ASN05439185, ASN08735135, ASN08745583 from ASINEX
database and 693, 234 from TCM database ligands occupy the
RNA binding region of VP40 with the almost similar
conformation with a glide score of -7.66, -7.46, -7.39, -7.11, -6.95,
-6.07 and -5.30 Kcal/mol. Maestro Ligand interaction 2-D
diagram was used to understand the in-depth interaction
pattern to the ligands and VP40.</p><sec id="s3a"><title><italic>Binding mode of ASN03576800 with the RNA binding region of VP40</italic>:</title><p>Docking results showed that the ligand ASN03576800 occupied
the RNA binding region of VP40 with a Glide score of -7.66 and
the Glide energy is -31.88 Kcal/mol. Two hydrogen bond
interactions were identified with the backbone amino acid
residue Ala156 and side chain amino acid residues Arg134 and
Arg148. Phe157 was involved in the π-π stacking interaction
with ligand. Four hydrophobic interactions with the amino acid
residues Pro97, Leu98, Ile152, Phe161 and one polar interaction
with the amino acid residue Gln155 in the RNA binding region
of VP40 were observed (<xref ref-type="fig" rid="F3">Figure 3</xref>).</p></sec><sec id="s3b"><title><italic>Binding mode of ASN06396768 with the RNA binding region of VP40</italic>:</title><p>The ligand ASN06396768 occupied the RNA binding region of
VP40 with a Glide score of -7.46 and the Glide energy is -40.64
Kcal/mol. Hydrogen bond interactions were identified with the
backbone amino acid residue Gly126 and side chain amino acid
residues Gln170 and Tyr171. Two hydrophobic interactions
with the amino acid residues Pro131 and Ala128, and two
positive charge interactions with Lys127 and His124 residues
were observed (<xref ref-type="fig" rid="F3">Figure 3</xref>).</p></sec><sec id="s3c"><title><italic>Binding mode of ASN05439185 with the RNA binding region of VP40</italic>:</title><p>Docking results showed that the ligand ASN05439185 occupied
the RNA binding region of VP40 with a Glide score of -7.39 and
the Glide energy is -44.72 Kcal/mol. Two hydrogen bond
interactions were identified with the backbone amino acid
residue Gly126 and side chain amino acid residue Gln170.
Pro131 and Tyr171 involved in the π-π stacking interaction with
the ligand. Four hydrophobic interactions with the amino acid
residues Phe125, Ala128, Leu132 and Phe172 formed and polar
interactions with the residues Thr123, Thr173 and Gln167.
His124 and Lys127 formed positive charge interaction with
ligand were observed (<xref ref-type="fig" rid="F3">Figure 3</xref>).</p></sec><sec id="s3d"><title><italic>Binding mode of ASN08735135 with the RNA binding region of VP40</italic>:</title><p>The ligand ASN08735135 occupied the RNA binding region of
VP40 with a Glide score of -7.11 and the Glide energy is -33.52
Kcal/mol. Two hydrogen bond interactions were identified
with the backbone amino acid residue Gly126 and side chain
amino acid residue Gln170. Tyr171 was involved in the π-π
stacking interaction with the ligand. Phe125, Ala128, Pro131
and Leu132 formed hydrophobic interactions. His124 and
Lys127 formed positive charge interactions with the ligand
(<xref ref-type="fig" rid="F3">Figure 3</xref>).</p></sec><sec id="s3e"><title><italic>Binding mode of ASN08745583 with the RNA binding region of VP40</italic>:</title><p>The ligand ASN08745583 occupied the RNA binding region of
VP40 with a Glide score of -6.95 and the Glide energy is -42.55
Kcal/mol. Two hydrogen bond interactions were identified
with the backbone amino acid residue Gly126 and side chain
amino acid residues Gln170 and Tyr171. Pro131 was involved in
the π-π stacking interaction with the ligand. Five hydrophobic
interactions with the amino acid residues Pro125, Ala128,
Leu132, Leu168 and Pro169 were observed. Thr123 and Gln167
formed polar interactions and His124 and Lys127 formed the
positive charge interactions with the ligand (<xref ref-type="fig" rid="F3">Figure 3</xref>).</p></sec><sec id="s3f"><title><italic>Binding mode of 693 with the RNA binding region of VP40</italic>:</title><p>Docking results showed that the ligand 693 occupied the RNA
binding region of VP40 with a Glide score of -6.07 and the Glide
energy is -24.52 Kcal/mol. Five hydrogen bond interactions
were identified with the backbone amino acid residue His124,
Phe172 and side chain amino acid residue Thr123, Thr173.
Phe125 and Tyr171 involved in the hydrophobic interaction
with the ligand were observed (<xref ref-type="fig" rid="F3">Figure 3</xref>).</p></sec><sec id="s3g"><title><italic>Binding mode of 234 with the RNA binding region of VP40</italic>:</title><p>The ligand 234 occupied the RNA binding region of VP40 with
a Glide score of -5.30 and the Glide energy is -35.27 Kcal/mol.
One hydrogen bond interaction was identified with the side
chain amino acid residue Thr173. Tyr171 was involved in the π-
π stacking interaction with the ligand. Four hydrophobic
interactions with the amino acid residues Phe125, Ala128,
Pro131 and Phe172 were observed. Thr123, His124 and Gln170
formed polar interactions and Lys127 formed the positive
charge interactions with the ligand (<xref ref-type="fig" rid="F3">Figure 3</xref>).</p><p>The <italic>Ebola</italic> virus matrix protein VP40 associates with the
assembly and budding process of enveloped viruses. VP40
contains two short sequence motifs (PPXY and PTAP) at its Nterminus
whose presence have been implicated in virus particle
release by interacting with cellular factors [<xref ref-type="bibr" rid="R23">23</xref>]. Matrix
protein/RNP interactions have been reported for a number of
enveloped viruses [<xref ref-type="bibr" rid="R26">26</xref>–<xref ref-type="bibr" rid="R29">29</xref>].
This process may generally involve
interactions with viral RNA, such as corona virus M/mRNA1
recognition, which seems to be crucial for the M-NP association
[<xref ref-type="bibr" rid="R39">39</xref>]. In addition, other studies implicated that the matrix
proteins interfere with the cellular RNA metabolism [<xref ref-type="bibr" rid="R40">40</xref>,
<xref ref-type="bibr" rid="R41">41</xref>].
The dimer interface is stabilized by the interaction with ssRNA
segment. The RNA mainly interacts with Arg134, Phe125 [<xref ref-type="bibr" rid="R23">23</xref>].
Arg134, Phe125 are the most important residues in the
interaction and both are positioned next to each other and
exposed close to the interface of the N-terminal domains in the
monomeric conformation it might play them in the transition
process. VP40 is a monomer in solution and it is containing two
domains [<xref ref-type="bibr" rid="R30">30</xref>] and interaction with cellular budding factors
[<xref ref-type="bibr" rid="R42">42</xref>–<xref ref-type="bibr" rid="R44">44</xref>]
with C-terminal domain is instrumental for membrane
association [<xref ref-type="bibr" rid="R25">25</xref>].</p><p>The compound FGI106, (Quino[8,7-h]quinoline-
1,7diamine,N,N-bis[3-(dimethylamino) propyl]-3,9-dimethyltetrahydrochloride)
is reported as an inhibitor of Ebola virus
replication without its specificity towards any of the potent
target proteins [<xref ref-type="bibr" rid="R45">45</xref>,
<xref ref-type="bibr" rid="R46">46</xref>]. Ribavirins, which function as host and
virus proteins, aryl methyldiene rhodanine derivative, termed
“LJ001”, LJ001 intercalates into lipid bilayers, probably via the
phenyl ring on its nonpolar end and positions the
pharmacophore on the opposite polar end for activity. It is
possible that an activation of the thioxo functionality occurs to
cause damage in the lipid environment of the virus or cell. The
actual efficacy of LJ001 for the prophylactic, postexposure, or
therapeutic treatment of enveloped viral diseases probably will
depend on formulation and pharmacological considerations as
well as on the pathogenic profile of the virus [<xref ref-type="bibr" rid="R47">47</xref>]. SAH
hydrolase inhibitor is to boost the immune response by
stimulating interferon production. SAH inhibitors induced IFN-
α given immediately reduce the Ebola and Zaire resulted only in
a 2-day in the onset of illness and death [<xref ref-type="bibr" rid="R48">48</xref>]. Cyanovirin-N
(CV-N) is a protein that is produced by cyanobacteria and it
binds to high-mannose oligosaccharides, treatment for 6 days
delayed the onset of illness and prolonged the time of survival –
however, it failed to protect mice from death [<xref ref-type="bibr" rid="R49">49</xref>].</p></sec><sec id="s3h"><title><italic>Predicted ADME properties</italic>:</title><p>Physically significant descriptors and pharmaceutically relevant
properties of the ten lead compounds were analyzed using
molsoft. Molecular weight, log <italic>P</italic> Octanol/water partition
coefficient, H-bond donors, H-bond acceptors, Mol Log S and
their positions according to Lipinski's rule of five were included
as significant descriptors <xref ref-type="supplementary-material" rid="SD1">Table 1</xref> (see supplementary material).
The ten selected compounds were in the acceptable range of
Lipinski's rule of five, indicating their potential for use as druglike
molecules [<xref ref-type="bibr" rid="R37">37</xref>].</p></sec></sec><sec id="s4"><title>Conclusions</title><p>Since, no potent inhibitors are available against <italic>Ebola</italic> virus,
molecular docking studies were performed to identify small
molecule inhibitors of the lipid bilayer interaction during the
viral assembly and budding process. HTVS screened
compounds from ASINEX and TCM database were subjected to
SP docking which resulted in 159 compounds. These
compounds were further taken for XP docking. Using XP
docking, based on the glide score, glide energy and H-bond
interactions with the amino acid residues of RNA binding site,
10 compounds were shortlisted. ADME properties test of the hit
molecules indicated that all the 10 compounds were within the
acceptable range of Lipinski's Rule of Five. This suggests that
the ten compounds could be potential inhibitors of the VP40
matrix protein. Out of the ten compounds, ASN03576800 (2-[2-
(1,3-benzodioxol-5-ylamino)-2-oxoethyl]sulfinylacetic acid) has
a good glide score and glide energy (-7.46 & -50.30 kcal/mol).
The ligand has a good contact with the specific amino acid
residue Arg134 and other residues like Gly126 and Thr173 with
the hydrogen bond distances of 2.0, 1.9 and 2.1 Å. The ligand
ASN03576800 could be a potent inhibitor for <italic>Ebola</italic> virus matrix
protein VP40 in process of viral assembly and budding process.</p></sec><sec sec-type="supplementary-material"><title>Supplementary material</title><supplementary-material content-type="local-data" id="SD1"><caption><title>Data 1</title></caption><media xlink:href="97320630009286S1.pdf" xlink:type="simple" id="d35e455" position="anchor" mimetype="application" mime-subtype="pdf"></media></supplementary-material></sec></body><back><ack><p>TT acknowledges SRM University and DRDO, India for their
financial support.</p></ack><fn-group><fn id="FN1" fn-type="other"><p><bold>Citation:</bold>Tamilvanan & Hopper, Bioinformation 9(6): 286-292 (2013)</p></fn></fn-group><ref-list><title>References</title><ref id="R01"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Borio</surname><given-names>L</given-names></name><etal></etal></person-group><source>JAMA</source><year>2002</year><volume>287</volume><fpage>2391</fpage><pub-id pub-id-type="pmid">11988060</pub-id></element-citation></ref><ref id="R02"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bray</surname><given-names>M</given-names></name><etal></etal></person-group><source>Antiviral Res</source><year>2003</year><volume>57</volume><fpage>53</fpage><pub-id pub-id-type="pmid">12615303</pub-id></element-citation></ref><ref id="R03"><label>3</label><element-citation 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pub-id-type="pmid">12719006</pub-id></element-citation></ref></ref-list></back><floats-group><fig id="F1" position="float"><label>Figure 1</label><caption><p>Amino acids involved in RNA-VP40 interactions.</p></caption><graphic xlink:href="97320630009286F1"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><p>Docking interaction of Lead compounds with matrix protein VP40 and their corresponding glide score and energy.</p></caption><graphic xlink:href="97320630009286F2"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><p>Docked conformation of ASN03576800, ASN06396768,
ASN05439185, ASN08735135, ASN08745583, 693 and 234
compounds in the RNA binding region of VP40.</p></caption><graphic xlink:href="97320630009286F3"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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