Computer-based design of novel HIV-1 entry inhibitors: neomycin conjugated to arginine peptides at two specific sites
Identifieur interne : 002B00 ( Main/Exploration ); précédent : 002A99; suivant : 002B01Computer-based design of novel HIV-1 entry inhibitors: neomycin conjugated to arginine peptides at two specific sites
Auteurs : Alexander Berchanski [Israël] ; Aviva Lapidot [Israël]Source :
- Journal of Molecular Modeling [ 1610-2940 ] ; 2009-03-01.
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Abstract
Abstract: Aminoglycoside–arginine conjugates (AAC and APAC) are multi-target inhibitors of human immunodeficiency virus type-1 (HIV-1). Here, we predict new conjugates of neomycin with two arginine peptide chains binding at specific sites on neomycin [poly-arginine-neomycin-poly-arginine (PA-Neo-PA)]. The rationale for the design of such compounds is to separate two short arginine peptides with neomycin, which may extend the binding region of the CXC chemokine receptor type 4 (CXCR4). We used homology models of CXCR4 and unliganded envelope glycoprotein 120 (HIV-1IIIB gp120) and docked PA-Neo-PAs and APACs to these using a multistep docking procedure. The results indicate that PA-Neo-PAs spread over two negatively charged patches of CXCR4. PA-Neo-PA–CXCR4 complexes are energetically more favorable than AACs/APAC–CXCR4 complexes. Notably, our CXCR4 model and docking procedure can be applied to predict new compounds that are either inhibitors of gp120–CXCR4 binding without affecting stromal cell-derived factor 1α (SDF-1α) chemotaxis activity, or inhibitors of SDF-1α–CXCR4 binding resulting in an anti-metastasis effect. We also predict that PA-Neo-PAs and APACs can interfere with CD4–gp120 binding in unliganded conformation. Figure The r5-Neo-r5-CXCR4 complex. CXCR4 is shown in CPK representation. The negatively charged residues are shown in red and positively charged residues in blue. The r5-Neo-r5 is shown in stick representation, neomycin core is colored yellow and arginine moieties are colored magenta. Two negatively charged patches separated by neutral and positively charged residues are visible.
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DOI: 10.1007/s00894-008-0401-1
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Computer-based design of novel HIV-1 entry inhibitors: neomycin conjugated to arginine peptides at two specific sites</title><author><name sortKey="Berchanski, Alexander" sort="Berchanski, Alexander" uniqKey="Berchanski A" first="Alexander" last="Berchanski">Alexander Berchanski</name></author><author><name sortKey="Lapidot, Aviva" sort="Lapidot, Aviva" uniqKey="Lapidot A" first="Aviva" last="Lapidot">Aviva Lapidot</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:627E62E8DDCCBDD702E903064164A0C8357E4C4D</idno><date when="2008" year="2008">2008</date><idno type="doi">10.1007/s00894-008-0401-1</idno><idno type="url">https://api.istex.fr/ark:/67375/VQC-WBV9ZP52-H/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">000A39</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000A39</idno><idno type="wicri:Area/Istex/Curation">000A39</idno><idno type="wicri:Area/Istex/Checkpoint">000814</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Checkpoint">000814</idno><idno type="wicri:doubleKey">1610-2940:2008:Berchanski A:computer:based:design</idno><idno type="wicri:Area/Main/Merge">002B26</idno><idno type="wicri:Area/Main/Curation">002B00</idno><idno type="wicri:Area/Main/Exploration">002B00</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Computer-based design of novel HIV-1 entry inhibitors: neomycin conjugated to arginine peptides at two specific sites</title><author><name sortKey="Berchanski, Alexander" sort="Berchanski, Alexander" uniqKey="Berchanski A" first="Alexander" last="Berchanski">Alexander Berchanski</name><affiliation wicri:level="1"><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Organic Chemistry, The Weizmann Institute of Science, 76100, Rehovot</wicri:regionArea><wicri:noRegion>Rehovot</wicri:noRegion></affiliation></author><author><name sortKey="Lapidot, Aviva" sort="Lapidot, Aviva" uniqKey="Lapidot A" first="Aviva" last="Lapidot">Aviva Lapidot</name><affiliation wicri:level="1"><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Organic Chemistry, The Weizmann Institute of Science, 76100, Rehovot</wicri:regionArea><wicri:noRegion>Rehovot</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Israël</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Molecular Modeling</title><title level="j" type="sub">Computational Chemistry - Life Sciences - Advanced Materials - New Methods</title><title level="j" type="abbrev">J Mol Model</title><idno type="ISSN">1610-2940</idno><idno type="eISSN">0948-5023</idno><imprint><publisher>Springer-Verlag</publisher><pubPlace>Berlin/Heidelberg</pubPlace><date type="published" when="2009-03-01">2009-03-01</date><biblScope unit="volume">15</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="281">281</biblScope><biblScope unit="page" to="294">294</biblScope></imprint><idno type="ISSN">1610-2940</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1610-2940</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>CXCR4/SDF-1α</term><term>HIV-1 entry inhibitors</term><term>Molecular modeling and docking</term><term>Poly-arginine aminoglycoside conjugates</term><term>Predicted compounds</term><term>gp120/CD4</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: Aminoglycoside–arginine conjugates (AAC and APAC) are multi-target inhibitors of human immunodeficiency virus type-1 (HIV-1). Here, we predict new conjugates of neomycin with two arginine peptide chains binding at specific sites on neomycin [poly-arginine-neomycin-poly-arginine (PA-Neo-PA)]. The rationale for the design of such compounds is to separate two short arginine peptides with neomycin, which may extend the binding region of the CXC chemokine receptor type 4 (CXCR4). We used homology models of CXCR4 and unliganded envelope glycoprotein 120 (HIV-1IIIB gp120) and docked PA-Neo-PAs and APACs to these using a multistep docking procedure. The results indicate that PA-Neo-PAs spread over two negatively charged patches of CXCR4. PA-Neo-PA–CXCR4 complexes are energetically more favorable than AACs/APAC–CXCR4 complexes. Notably, our CXCR4 model and docking procedure can be applied to predict new compounds that are either inhibitors of gp120–CXCR4 binding without affecting stromal cell-derived factor 1α (SDF-1α) chemotaxis activity, or inhibitors of SDF-1α–CXCR4 binding resulting in an anti-metastasis effect. We also predict that PA-Neo-PAs and APACs can interfere with CD4–gp120 binding in unliganded conformation. Figure The r5-Neo-r5-CXCR4 complex. CXCR4 is shown in CPK representation. The negatively charged residues are shown in red and positively charged residues in blue. The r5-Neo-r5 is shown in stick representation, neomycin core is colored yellow and arginine moieties are colored magenta. 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