Abstract:
BACKGROUND:The pathogenicity of influenza A and B viruses depends on the function of influenza neuraminidase (NA). Emerging resistant influenza A viruses of subtype H1N1 increasingly challenge the effectiveness of established NA inhibitors. Recent computational studies have indicated several weak points of NA that can be exploited for rational inhibitor design to conquer this imminent threat, such as the opening of the binding pocket due to the flexibility of the 150-, 245- and 430-loops. METHODS:We employed shape-focused virtual screening based on a recently discovered lead compound, katsumadain A, to identify novel promising compounds with significant inhibitory efficacy on NA and resistance-breaking capacity on oseltamivir-resistant strains. A potential binding mode of these compounds was derived employing ligand-based techniques and protein-ligand docking using representative protein conformations selected from molecular dynamics simulations. RESULTS:Five novel compounds were identified by virtual screening. Their IC(50) values, determined in chemiluminescence-based NA inhibition assays, are in the range of 0.18-17 µM. In particular, artocarpin exhibits high affinity toward three H1N1 oseltamivir-sensitive influenza A viruses. It also inhibits the NA of an oseltamivir-resistant H1N1 isolate.
journal_name
Future Med Chemjournal_title
Future medicinal chemistryauthors
Kirchmair J,Rollinger JM,Liedl KR,Seidel N,Krumbholz A,Schmidtke Mdoi
10.4155/fmc.10.292subject
Has Abstractpub_date
2011-03-01 00:00:00pages
437-50issue
4eissn
1756-8919issn
1756-8927journal_volume
3pub_type
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pub_type: 杂志文章,评审
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pub_type: 杂志文章,评审
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更新日期:2015-01-01 00:00:00
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pub_type: 杂志文章
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journal_title:Future medicinal chemistry
pub_type: 杂志文章,评审
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更新日期:2015-01-01 00:00:00
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journal_title:Future medicinal chemistry
pub_type: 杂志文章
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更新日期:2020-08-01 00:00:00
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更新日期:2016-06-01 00:00:00