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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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Swiss Institute of Bioinformatics and Biozentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland
Novartis Institute for Tropical Diseases, 10 Biopolis Road, Chromos #05-01, 138670 Singapore
§ Schrödinger LLC, 120 West 45th Street, 29th Floor, New York, New York 10036-4041
*To whom correspondence should be addressed: Swiss Institute of Bioinformatics and Biozentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland. Telephone: +41 61 267 15 81. Fax: +41 61 267 15 84. E-mail: [email protected]
Cite this: J. Med. Chem. 2010, 53, 4, 1483–1495
Publication Date (Web):January 28, 2010
https://doi.org/10.1021/jm900776m
Copyright © 2010 American Chemical Society

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    Abstract

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    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.

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    Implementation of decision tree and random forest aggregation predictors, and structures of tested compounds (Tables S1−S4). This material is available free of charge via the Internet at http://pubs.acs.org.

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