Inhibitors of SARS-3CLpro: Virtual Screening, Biological Evaluation and Molecular Dynamics Simulation Studies
Identifieur interne : 000B40 ( Pmc/Checkpoint ); précédent : 000B39; suivant : 000B41Inhibitors of SARS-3CLpro: Virtual Screening, Biological Evaluation and Molecular Dynamics Simulation Studies
Auteurs : Prasenjit Mukherjee ; Falgun Shah ; Prashant Desai ; Mitchell AverySource :
- Journal of chemical information and modeling [ 1549-9596 ] ; 2011.
Abstract
SARS-CoV from the coronaviridae family has been identified as the etiological agent of Severe Acute Respiratory Syndrome (SARS), a highly contagious upper respiratory disease that reached epidemic status in 2002. SARS-3CLpro, a cysteine protease indispensible to the viral life cycle, has been identified as one of the key therapeutic target against SARS. A combined ligand and structure based virtual screening was carried out against the Asinex Platinum collection. Multiple low micromolar inhibitors of the enzyme were identified through this search, one of which also showed activity against SARS-CoV in a whole cell CPE assay. Furthermore, multi nanosecond explicit solvent simulations were carried out using the docking poses of the identified hits to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Cumulative analysis of the evaluated compounds and the simulation studies led to the identification of certain protein-ligand interaction patterns which would be useful in further structure based design efforts.
Url:
DOI: 10.1021/ci1004916
PubMed: 21604711
PubMed Central: 3929308
Affiliations:
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<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101230060</journal-id><journal-id journal-id-type="pubmed-jr-id">32252</journal-id><journal-id journal-id-type="nlm-ta">J Chem Inf Model</journal-id><journal-id journal-id-type="iso-abbrev">J Chem Inf Model</journal-id><journal-title-group><journal-title>Journal of chemical information and modeling</journal-title></journal-title-group><issn pub-type="ppub">1549-9596</issn><issn pub-type="epub">1549-960X</issn></journal-meta><article-meta><article-id pub-id-type="pmid">21604711</article-id><article-id pub-id-type="pmc">3929308</article-id><article-id pub-id-type="doi">10.1021/ci1004916</article-id><article-id pub-id-type="manuscript">NIHMS298995</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Inhibitors of SARS-3CL<sup>pro</sup>: Virtual Screening, Biological Evaluation and Molecular Dynamics Simulation Studies</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Mukherjee</surname><given-names>Prasenjit</given-names></name><xref ref-type="author-notes" rid="FN1">$</xref></contrib><contrib contrib-type="author"><name><surname>Shah</surname><given-names>Falgun</given-names></name></contrib><contrib contrib-type="author"><name><surname>Desai</surname><given-names>Prashant</given-names></name><xref ref-type="author-notes" rid="FN2">#</xref></contrib><contrib contrib-type="author"><name><surname>Avery</surname><given-names>Mitchell</given-names></name><xref ref-type="corresp" rid="cor1">*</xref></contrib><aff id="A1">Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677</aff></contrib-group><author-notes><corresp id="cor1"><label>*</label>Corresponding author phone: 662-915-5879, fax: 662-915-5638, <email>mavery@olemiss.edu</email></corresp><fn id="FN1" fn-type="present-address"><label>$</label><p id="P1">Current address: Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, CA 94608</p></fn><fn id="FN2" fn-type="present-address"><label>#</label><p id="P2">Current address: Lilly Research Laboratories, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>29</day><month>6</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>23</day><month>5</month><year>2011</year></pub-date><pub-date pub-type="ppub"><day>27</day><month>6</month><year>2011</year></pub-date><pub-date pub-type="pmc-release"><day>19</day><month>2</month><year>2014</year></pub-date><volume>51</volume><issue>6</issue><fpage>1376</fpage><lpage>1392</lpage><pmc-comment>elocation-id from pubmed: 10.1021/ci1004916</pmc-comment>
<abstract><p id="P3">SARS-CoV from the coronaviridae family has been identified as the etiological agent of Severe Acute Respiratory Syndrome (SARS), a highly contagious upper respiratory disease that reached epidemic status in 2002. SARS-3CL<sup>pro</sup>, a cysteine protease indispensible to the viral life cycle, has been identified as one of the key therapeutic target against SARS. A combined ligand and structure based virtual screening was carried out against the Asinex Platinum collection. Multiple low micromolar inhibitors of the enzyme were identified through this search, one of which also showed activity against SARS-CoV in a whole cell CPE assay. Furthermore, multi nanosecond explicit solvent simulations were carried out using the docking poses of the identified hits to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Cumulative analysis of the evaluated compounds and the simulation studies led to the identification of certain protein-ligand interaction patterns which would be useful in further structure based design efforts.</p></abstract><funding-group><award-group><funding-source country="United States">National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID</funding-source><award-id>N01 AI030048 || AI</award-id></award-group></funding-group></article-meta></front></pmc><affiliations><list></list><tree><noCountry><name sortKey="Avery, Mitchell" sort="Avery, Mitchell" uniqKey="Avery M" first="Mitchell" last="Avery">Mitchell Avery</name><name sortKey="Desai, Prashant" sort="Desai, Prashant" uniqKey="Desai P" first="Prashant" last="Desai">Prashant Desai</name><name sortKey="Mukherjee, Prasenjit" sort="Mukherjee, Prasenjit" uniqKey="Mukherjee P" first="Prasenjit" last="Mukherjee">Prasenjit Mukherjee</name><name sortKey="Shah, Falgun" sort="Shah, Falgun" uniqKey="Shah F" first="Falgun" last="Shah">Falgun Shah</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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