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Novel inhibitors of dengue virus methyltransferase: discovery by in vitro-driven virtual screening on a desktop computer grid.

Abstract

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 IC(50) values of <100 microM, of which four exhibited IC(50) values of <10 microM 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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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Swiss Institute of Bioinformatics and Biozentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.

    , , , , , , ,

    Source

    Journal of medicinal chemistry 53:4 2010 Feb 25 pg 1483-95

    MeSH

    Binding Sites
    Computers
    Databases, Factual
    Dengue Virus
    Drug Discovery
    Ligands
    Methyltransferases
    Models, Molecular
    Mutation
    Pharmaceutical Preparations
    Protein Binding
    Structure-Activity Relationship

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    20108931

    Citation

    TY - JOUR T1 - Novel inhibitors of dengue virus methyltransferase: discovery by in vitro-driven virtual screening on a desktop computer grid. AU - Podvinec,Michael, AU - Lim,Siew Pheng, AU - Schmidt,Tobias, AU - Scarsi,Marco, AU - Wen,Daying, AU - Sonntag,Louis-Sebastian, AU - Sanschagrin,Paul, AU - Shenkin,Peter S, AU - Schwede,Torsten, PY - 2010/1/30/entrez PY - 2010/1/30/pubmed PY - 2010/3/24/medline SP - 1483 EP - 95 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 53 IS - 4 N2 - 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 IC(50) values of <100 microM, of which four exhibited IC(50) values of <10 microM 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. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/20108931/Novel_inhibitors_of_dengue_virus_methyltransferase:_discovery_by_in_vitro_driven_virtual_screening_on_a_desktop_computer_grid_ L2 - https://dx.doi.org/10.1021/jm900776m ER -