25 February 2010

Distributed computing: finding medicines for fever and hepatitis

"Just about science" based on the materials of the World Community Grid: Discovering Dengue Drugs – Together – Phase 2The organizers of the distributed computing system World Community Grid announced the launch of the project Discovering Dengue Drugs – Together – Phase 2, in which the search for new drugs for dangerous diseases caused by flaviviruses (Flaviviridae) will continue.

The project is supported by the University of Texas Medical Branch (UTMB) in Galveston and the University of Chicago in Illinois, USA.

The project aims to detect potential medicinal compounds that block the reproduction of viruses of the Flaviviridae family in the human body. These include viruses that cause dangerous diseases such as Dengue fever, yellow fever, West Nile fever, hepatitis C, etc. About 40% of the world's population live in regions where there is a high probability of contracting one of the listed viruses. Every year, more than 1.5 million people are treated for Dengue fever. According to some estimates, up to 2% of the world's population is infected with hepatitis C. Yellow fever and West Nile fever cause great harm to developing countries. Unfortunately, there are no effective drugs for the treatment of these diseases, and palliative therapy is too expensive and at the same time can only slightly reduce mortality rates among patients.

As part of the Discovering Dengue Drugs – Together – Phase 2 project, scientists have relied on the search for NS3 viral protease inhibitors.

Inhibitors (Latin inhibere – to restrain, stop) are substances that slow down or prevent the development of any process or chemical reaction.

NS3 protease is an enzyme that plays a key role in the replication (reproduction) of the virus in the human body. The amino acid sequence and atomic structure of NS3 are practically the same for all flaviviruses. In addition, the structure of the protease is well known, so researchers hope to use computational methods to find effective drugs – chemical compounds that block the work of NS3.

Scientists from UTMB and the University of Chicago have already discovered substances that slow down the work of the protease of viruses that cause Dengue and West Nile fever in cell cultures. However, an additional search is needed for promising medicines to which flaviviruses have minimal resistance. In this matter, scientists are actively cooperating with the World Community Grid community, whose army of thousands of participants provides computing resources of their computers for scientific research.

In August 2009, the first phase of the project ended. The calculations were performed using a specialized program for molecular docking – AutoDock, developed by Dr. Olson and his collaborators from the Scripps Research Institute).

Molecular docking (docking) is a computer modeling method that allows predicting the orientation and position of one molecule relative to another that is most advantageous for the formation of a stable complex, including for complexes of low–molecular compounds and active centers of protein molecules.

During the calculations, the interaction with the NS3 protease was simulated for about 3 million potentially effective small molecules, from which several thousand of the most promising were selected.

Unfortunately, most often up to 90-95% of compounds selected at the first stage of virtual (“in silico”) screening of candidate substances turn out to be useless in laboratory studies. Therefore, before starting in vitro testing, it is necessary to choose the most effective molecules from the found ones. This is what the second phase of the project is designed for. (However, UTMB has already started "test tube" tests of some of the substances found that showed high activity in biochemical tests.)

During the work of Discovering Dengue Drugs – Together – Phase 2, it is planned to weed out false–positive compounds found in the first phase of the project using another program for molecular docking - CHARMM, developed by Martin Karplus and his colleagues at Harvard. Based on the results of the calculations, the molecules showing the greatest affinity with the flavivirus protease will be selected. It is based on the results of the second phase of the project that the UTMB laboratory will receive chemical compounds that are destined to eventually become new medicines for deadly fevers.

For information on how to start participating in World Community Grid projects (including Discovering Dengue Drugs – Together – Phase 2), see the end of the article "Distributed Computing: Volunteers in the Service of Science".

Portal "Eternal youth" http://vechnayamolodost.ru25.02.2010

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