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Virtual screening and bioassay study of novel inhibitors for dengue virus mRNA cap (nucleoside-2'O)-methyltransferase
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 24, 7795-7802 p.Article in journal (Refereed) Published
Abstract [en]

We report high-throughput structure-based virtual screening of putative Flavivirus 2'-O-methyltransferase inhibitors together with results from subsequent bioassay tests of selected compounds. Potential inhibitors for the S-adenosylmethionine binding site were explored using 2D similarity searching, pharmacophore filtering and docking. The inhibitory activities of 15 top-ranking compounds from the docking calculations were tested on a recombinant methyltransferase with the RNA substrate (7Me)GpppAC(5). Local and global docking simulations were combined to estimate the ligand selectivity for the target site. The results of the combined computational and experimental screening identified a novel inhibitor, with a previously unknown scaffold, that has an IC(50) value of 60 microM.

Place, publisher, year, edition, pages
2007. Vol. 15, no 24, 7795-7802 p.
Keyword [en]
Flavivirus methyltransferase inhibitor, drug design, virtual screening, docking
National Category
Biological Sciences
URN: urn:nbn:se:uu:diva-105256DOI: 10.1016/j.bmc.2007.08.049ISI: 000253489200030PubMedID: 17888664OAI: oai:DiVA.org:uu-105256DiVA: diva2:220838
Erratum in: Bioorg Med Chem. 2008 Mar 15;16(6):3462Available from: 2009-06-02 Created: 2009-06-02 Last updated: 2010-08-13Bibliographically approved

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