Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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Biological Assay
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Dengue Virus / drug effects*
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Dengue Virus / enzymology
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Dengue Virus / genetics
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Drug Design*
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Inhibitory Concentration 50
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Ligands
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Methyltransferases / antagonists & inhibitors
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Methyltransferases / biosynthesis*
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Models, Molecular
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Molecular Structure
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RNA, Messenger / biosynthesis*
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Recombinant Proteins / chemical synthesis
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Recombinant Proteins / chemistry
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Recombinant Proteins / pharmacology
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Virus Assembly / drug effects
Substances
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Enzyme Inhibitors
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Ligands
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RNA, Messenger
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Recombinant Proteins
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Methyltransferases
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cap I RNA (nucleoside-2'-)methyltransferase