| pubmed-article:20627595 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:20627595 | lifeskim:mentions | umls-concept:C0220847 | lld:lifeskim |
| pubmed-article:20627595 | lifeskim:mentions | umls-concept:C0220908 | lld:lifeskim |
| pubmed-article:20627595 | lifeskim:mentions | umls-concept:C0268563 | lld:lifeskim |
| pubmed-article:20627595 | lifeskim:mentions | umls-concept:C0220781 | lld:lifeskim |
| pubmed-article:20627595 | lifeskim:mentions | umls-concept:C1335439 | lld:lifeskim |
| pubmed-article:20627595 | lifeskim:mentions | umls-concept:C1883254 | lld:lifeskim |
| pubmed-article:20627595 | lifeskim:mentions | umls-concept:C0243077 | lld:lifeskim |
| pubmed-article:20627595 | lifeskim:mentions | umls-concept:C0679622 | lld:lifeskim |
| pubmed-article:20627595 | lifeskim:mentions | umls-concept:C1553497 | lld:lifeskim |
| pubmed-article:20627595 | lifeskim:mentions | umls-concept:C0205314 | lld:lifeskim |
| pubmed-article:20627595 | pubmed:issue | 13 | lld:pubmed |
| pubmed-article:20627595 | pubmed:dateCreated | 2011-3-25 | lld:pubmed |
| pubmed-article:20627595 | pubmed:abstractText | Hepatitis C virus (HCV) NS5B polymerase is a key target for the development of therapeutic agents aimed at the treatment of HCV infections. Here we report on the identification of novel allosteric inhibitors of HCV NS5B through a combination of structure-based virtual screening, synthesis and structure-activity relationship (SAR) optimization approach. Virtual screening of 260,000 compounds from the ChemBridge database against the tetracyclic indole inhibitor binding pocket of NS5B (allosteric pocket-1, AP-1), sequentially down-sized the library by 4 orders of magnitude to yield 23 candidates. In vitro evaluation of the NS5B inhibitory activity of the in-silico selected compounds resulted in 17% hit rate, identifying two novel chemotypes. Of these, compound 3, bearing the rhodanine scaffold, proved amenable for productive SAR exploration and synthetic modification. As a result, 25 derivatives that exhibited IC?? values ranging from 7.7 to 68.0 ?M were developed. Docking analysis of lead compound 28 within the tetracyclic indole- and benzylidene-binding allosteric pockets (AP-1 and AP-3, respectively) of NS5B revealed topological similarities between these two pockets. Compound 28, a novel rhodanine analog with NS5B inhibitory potency in the low micromolar level range may be a promising lead for future development of more potent NS5B inhibitors. | lld:pubmed |
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| pubmed-article:20627595 | pubmed:language | eng | lld:pubmed |
| pubmed-article:20627595 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:20627595 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:20627595 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
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| pubmed-article:20627595 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:20627595 | pubmed:month | Jul | lld:pubmed |
| pubmed-article:20627595 | pubmed:issn | 1464-3391 | lld:pubmed |
| pubmed-article:20627595 | pubmed:author | pubmed-author:PatelMaulik... | lld:pubmed |
| pubmed-article:20627595 | pubmed:author | pubmed-author:TaleleTanaji... | lld:pubmed |
| pubmed-article:20627595 | pubmed:author | pubmed-author:AroraPayalP | lld:pubmed |
| pubmed-article:20627595 | pubmed:author | pubmed-author:SinghSatyakam... | lld:pubmed |
| pubmed-article:20627595 | pubmed:author | pubmed-author:Kaushik-BasuN... | lld:pubmed |
| pubmed-article:20627595 | pubmed:author | pubmed-author:KulkarniShrid... | lld:pubmed |
| pubmed-article:20627595 | pubmed:author | pubmed-author:ChudayeuMaksi... | lld:pubmed |
| pubmed-article:20627595 | pubmed:copyrightInfo | Copyright © 2010 Elsevier Ltd. All rights reserved. | lld:pubmed |
| pubmed-article:20627595 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:20627595 | pubmed:day | 1 | lld:pubmed |
| pubmed-article:20627595 | pubmed:volume | 18 | lld:pubmed |
| pubmed-article:20627595 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:20627595 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:20627595 | pubmed:pagination | 4630-8 | lld:pubmed |
| pubmed-article:20627595 | pubmed:dateRevised | 2011-8-1 | lld:pubmed |
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