Case studies

For a European pharma company, we identified commercial compounds that target splicing factor proteins against Leukemia and certain genetic diseases.
We investigated pockets of interest via pharmacophore-based approaches and virtual screening to identify a series of molecules that, when tested experimentally, interfered with cell growth (50 μM in HeLa cells).

 

This work was confidential and has not been published.

For a French pharma company, we virtually screened non-selective compound libraries to identify lead molecules that, when later screened in vitro, selectively inhibited protein kinases (IC50 approx. 1 μM).
To optimize these leads, we performed molecular docking, 3D-QSAR and Molecular Dynamics simulations to create a new round of analogues that, when subsequently tested in vitro, exhibited selective inhibition at 50 nM.

 

This work was confidential and has not been published.

Wilson disease, an orphan genetic disease that leads to accumulation of copper in the liver, is caused by mutations in the gene coding for the copper-transporting protein ATP7B. Working with academic partners, we helped elucidate the mode of action of the ATP7B domain. Specifically, based on our Molecular Dynamics simulations, we characterized an allosteric regulatory mechanism involving the N-domain of the Mg2+-ATP coordination site.

 

This work was published in 2011:
Hercend et al. PLoS ONE (2011) 6(10), e26245

Cucurbitacins, a set of triterpenoid sterols isolated from plants, are potent inhibitors of cell migration and division. We helped a French public (INSERM) lab to study the impact of cucurbitacins on signal transduction and actin dynamics. Our Molecular Docking simulations of cucurbitacins helped our colleagues to ascertain how these compounds inhibit the enzyme LIM-kinase.

 

This work was published in 2016:
Sari-Hassoun et al. Biochemical Pharmacology (2016) 102, 45–63.

Progeria (Hutchinson-Gilford progeria syndrome), is a deadly genetic disease that causes early aging in children. Post-translational farnesylation of the protein progerin has been linked to the severity of progeria. Using Molecular Docking, we helped a team from the French Institute for Stem Cell Therapy and Exploration of Monogenic Diseases (I-STEM) to identify and study a novel set of small-molecule inhibitors of the enzymes responsible for this farnesylation: farnesyl pyrophosphate synthase and farnesyl transferase.

 

This work was published in 2016:
Blondel et al. Cell Death and Disease (2016) 7, e2105