MissionMore than 4.3 million medicines tested thanks to calculation grids

in Press Release Feb 8, 2024 By None From Eurekalert.org

The second phase of the Wisdom experiment, carried out as an international cooperation project involving IN2P3 /CNRS, was completed on January 31. Thanks to the association of several international calculation grids , including the European grid Egee , it was possible to analyze close to 80,000 potential medicines for the treatment of malaria per hour over the course of 10 weeks. Wisdom opened up new therapeutic possibilities for the treatment of this illness and also for the fight against other tropical diseases.

Wisdom’s strategy is based on a virtual screening of molecules with encouraging therapeutic performances: it allows researchers to calculate the probability that a molecule (called an active molecule or “ligand”) will bind to a target protein, thereby altering its biological activity, and, in the case of malaria, the proliferation of the parasite. Over the ten weeks of the experiment, 4.3 million active molecules (potential medicines) were tested, and more than 140 million linkages between these molecules and the target proteins to combat malaria were calculated. Through this process, it was possible to reject a large number of compounds in record time, allowing researchers to focus the biological tests on the most promising chemical compounds. While accelerating the process of selection of the “best” molecules, this strategy can also substantially reduce the cost of developing new medicines against this disease which has an especially large impact on developing countries.

The impact of the approach used in Wisdom goes beyond malaria. This strategy can be extended to all diseases, opening up major possibilities for industry. Furthermore, Wisdom allows for a systematic investigation of all potentially valuable compounds whereas, until now, the search for new medicines in the academic sector was carried out on a small scale.

In 2005, the first large-scale deployment on the Egee grid screened more than 41 million chemical compounds in only six weeks, representing the equivalent of 80 years of calculations on a standard computer. Of the 5,000 best chemical compounds selected in this screening, three families of molecules in particular caught the attention of the researchers: two were already known for their action on the targeted protein while the third is completely new. Analysis of the most promising compounds is continuing at the University of Modena in Italy and at the Laboratoire de physique corpusculaire (LPC) in Clermont-Ferrand (IN2P3/CNRS, Blaise Pascal University) before being sent for in vitro tests at the enzymology laboratory of Chonnam National University (South Korea).

AN INTERNATIONAL MOBILIZATION

The success of this first initiative attracted the interest of the international research community, which led to a deployment for avian influenza in April and May 2006 and then this second deployment for malaria for new target proteins proposed by French, Italian, Venezuelan and South African laboratories. Many calculation grids joined this effort: the regional grid Auvergrid in Auvergne, the EELA, EUChinaGRID, EUMedGRID and ASGC TWGrid grids made their calculation resources available, supplementing those of the Egee grid. Lastly, two other European projects, Embrace and BioinfoGRID, are contributing to improving the selection of the most promising molecules from among the millions of commercially-available chemical compounds.

For this second phase of the Wisdom project, more than 5,000 computers were mobilized simultaneously in 27 countries, producing more than 2,000 gigabits of data, which represents the equivalent of 413 years of calculations on a single computer. In France, several CNRS laboratories made a very significant contribution: the Calculation Center of IN2P3 manages the resources made available for this initiative and the LPC supervises the use of the resources for the various scientific calculations. The contribution of all of the French laboratories on the Egee grid represents about 15% of the 413 years of calculations.

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CONTACTS

Researcher Contact
Vincent Breton
Telephone: 06 863257 51
breton@clermont.in2p3.fr

IN2P3/CNRS Communication Contact
Christina Cantrel
Telephone: 01 449647 60
ccantrel@admin.in2p3.fr

Press Contact
Priscilla Dacher
Telephone: 01 449646 06
priscilla.dacher@cnrs-dir.fr

Simulation of the binding of a chemical compound with a mutated structure of the DHFR of Plasmodium falciparum which is the target of anti-malaria medicines. At left, an inhibitor of the non-mutated DHFR: the part in white shows the conformation of the ligand before the binding, the part in color shows its conformation when it is bound to the mutated DHFR. © Vinod Kasam - IN2P3/CNRS

BIBLIOGRAPHY

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