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In silico datas have been valitated experimentally in wet laboratory. 30 compounds coming from MD step were selected manually, based on key interactions, and tested against recombinant aspartic protease Plasmepsin II expressed from the encoding gene. 6 compounds out of 30 showed similar or better inhibitions compared to Pepstatin A, a general inhibitor of aspartic proteases. All tested 30 compounds demonstrated plasmepsin II inhibition activity at nanomolar concentrations. In the meanwhile, 10 compounds out of this 30 were tested in vivo to figure out the impact on Plasmodium falciparum growth as well as the potential toxicity on human cells model. Premilinary results are very promising to go further in drug discovery process. Biological tests will be performed in near future for other targets as well.
1. Short overview
Malaria is a deadly tropical disease affecting and killing millions of people every year. Malaria is traditionally ignored by the pharmaceutical industries as it is restricted to mainly poor and developing countries and also due to the heavy costs (~$800 million) involved in the drug discovery activities. Novel and cost effective tools are needed for finding potential new drugs for malaria.
Provide a set of generic keywords that define your contribution (e.g. Data Management, Workflows, High Energy Physics)
Malaria,Plasmepsin,virtual screening,docking,molecular dynamics,in vitro,EGEE,Auvergrid,Wisdom
4. Conclusions / Future plans
Grids have significantly reduced the overall time required for database screening against a particular target. Computing resources from Biomed virtual organization were used exclusively. The molecular docking was deployed on the EGEE grid infrastructure, refinement by Molecular Dynamics on the French regional grid Auvergrid, both using the WISDOM production environment. The successful experimental results reveal the suitable combination of EGEE infrastructure and in silico drug discovery.