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.
|lipophilic surface||371 Å2|
|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.
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.
|cell IC50||< 1µM|
|selectivity index||> 20|
|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:
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.
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!
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!