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virtual screening case study

  • As part of a Wellcome Trust funded research project, fragment based screening and subsequent lead optimization at Vironika LLC (Philadelphia, USA) led to the identification of a number of potent inhibitors of a DNA binding protein essential for the maintenance of Epstein-Barr viral infections (Series A). However, Series A was hampered by high plasma protein binding, modest solubility and short half-life. Parallel to medicinal chemistry efforts to overcome these issues, a virtual screening exercise was performed at BioSolveIT to identify potential new & chemically distinct lead series.

  • a challenging target
    pocket properties
    volume 405 Å3
    surface 523 Å2
    lipophilic surface 371 Å2
    depth 13 Å
    overall drug score 0.65

    A DoGSiteScorer pocket detection and analysis of druggability suggests that this is likely to be a hard target – the binding interface is a relatively shallow lipophilic pocket with modest overall volume.

  • 25% Hit Rate! 6 actives < 10 µM!

    Docking of the eMolecules collection of commercially available drug-like small molecules into the active site with FlexX and re-scoring the poses with BioSolveIT's unique proprietary scoring function (HYDE) generated a list of compounds with predicted binding affinity of micromolar or better.

    Of the 67 compounds purchased, 17 had an IC50 of less than 50 µM in an HTRF assay of enzyme activity, a 25% hit rate! 6 compounds were found to be active at sub-10 µM levels, a 9% hit rate.

  • quality hits – MedChem amenable!
    cell IC50 < 1µM
    selectivity index > 20
    molecular weight 371
    calculated logS 6.0
    calculated logD7.4 4.6
    calculated logP 4.9
    polar surface area 55

    Hit identified were not only active in enzyme assays of activity, a number showed sub-micromolar activity in cell assays, with up to 25-fold selectivity over counter screening cell lines. All hits were highly MedChem friendly:

    • excellent potency in cell assays (permeable!)
    • good balance of physicochemical properties
    • short synthetic routes for rapid analog synthesis
    • interesting selectivity profiles across hit series

  • intuitive and interactive

    The visualisation in our SeeSAR software tool makes it super-easy to see which ligand atoms are contributing positively (green) and negatively (red) to the binding affinity (previous slide) as well as which bonds are in less than ideal conformations (above) – it is made obvious that the biaryl bond of this hit is in an unfavourable conformation.

  • rapid fixes for problem torsions!
    Fluorine substitution on a ring-torsion problem fixed!

    Working with BioSolveIT has been exceptional – their skills and experience in computational and medicinal chemistry provided the perfect complement to the Vironika discovery team and helped us overcome numerous challenges. The virtual screening they performed identified a number of potent series for us that not only helped us break out into new chemical space, but also opened up interesting new opportunities in targeting other viral proteins. I recommend them without hesitation!

    Troy Messick, Vice President, Vironika LLC

  • contact us today!

    For a free, no-obligation assessment of how virtual screening or one of our other industry leading structure based design solutions could accelerate your small molecule discovery efforts and open up new areas of chemical space, contact us today!


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