American Chemical Society
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Novel Inhibitors of Dengue Virus Methyltransferase: Discovery by in Vitro-Driven Virtual Screening on a Desktop Computer Grid

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journal contribution
posted on 2010-02-25, 00:00 authored by Michael Podvinec, Siew Pheng Lim, Tobias Schmidt, Marco Scarsi, Daying Wen, Louis-Sebastian Sonntag, Paul Sanschagrin, Peter S. Shenkin, Torsten Schwede
Dengue fever is a viral disease that affects 50−100 million people annually and is one of the most important emerging infectious diseases in many areas of the world. Currently, neither specific drugs nor vaccines are available. Here, we report on the discovery of new inhibitors of the viral NS5 RNA methyltransferase, a promising flavivirus drug target. We have used a multistage molecular docking approach to screen a library of more than 5 million commercially available compounds against the two binding sites of this enzyme. In 263 compounds chosen for experimental verification, we found 10 inhibitors with IC50 values of <100 μM, of which four exhibited IC50 values of <10 μM in in vitro assays. The initial hit list also contained 25 nonspecific aggregators. We discuss why this likely occurred for this particular target. We also describe our attempts to use aggregation prediction to further guide the study, following this finding.