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Research: Discovering Dengue Drugs - Together - Phase 2: Project FAQs
 
Discovering Dengue Drugs - Together - Phase 2



This project has the potential to yield novel antiviral drugs for infectious diseases that greatly impact global health. Specifically, the aim is to identify and develop antiviral drugs against Dengue, Hepatitis C, West Nile, and Yellow fever viruses. In addition, this study will provide the foundation for a new and more efficient approach to drug development for other diseases that plague the world.

This project is distributed using the BOINC client, which is available for download on this site for computers with Windows, Macintosh, or Linux operating systems. For system requirements, click here.

The first phase performs a faster screening on a larger set of potential drug candidates and the second phase performs a more time consuming screening of the best candidates identified in the first phase. See the following FAQ for more information: "What will World Community Grid's calculations produce?".

Information for Phase 1 of the Dengue Fever Project may be found by selecting "Research" from the upper navigation bar and searching for "Discovering Dengue Drugs - Together" under the heading COMPLETED RESEARCH or by clicking here.

The calculations done on World Community Grid will predict which small molecule compounds, out of the millions contained in a library database, should be tested for their ability to inhibit the flavivirus protease. This is a major step towards the ultimate goal of discovering new drugs to stop flavivirus infections.

Phase 1 of this project predicted how each small drug molecule might bind to the active site of the viral protease. This phase also produced preliminary "energies" that coarsely rank the strength of the intermolecular interactions between the compounds and viral protease.

Phase 2 will accurately predict free energies of binding between each drug compound and the viral protease. This calculation utilizes the binding orientations calculated in Phase 1. Due to computation time required for each free energy of binding calculation, only compounds with "good" scores from Phase 1 will be selected for Phase 2 calculations.

As an analogy, Phase 1 will tell us how two people might hold hands, whereas Phase 2 will tell us whether or not they want to hold hands.

Phase 2 of our project is designed to reduce the number of Phase 1 false positives (i.e., dead ends) that are tested in our laboratory. Phase 2 will take several thousand Phase 1 hits, run each hit through computationally demanding free energy calculations, and remove many of the false positives from the hit list. Phase 2 is expected to produce an updated list of hits that contains ~80% true positives. Testing Phase 2 hits in the laboratory will be much more productive, efficient, and rewarding than testing Phase 1 hits. For instance, to find 25 small molecules that stop dengue virus replication in the laboratory, we would need to synthesize and test either 250-500 Phase 1 hits or ~30 Phase 2 hits.

Phase 1 began in August 2007 and finished in August 2009. Phase 2 started in February 2010 and may finish by the end of 2010.

After completion of the project and internal analysis by the research groups, all data will be made available on the Discovering Dengue Drugs-Together web site.

Binding free energy is a thermodynamic measure of the difference in energy between a bound and an unbound state. In this project, it is the energy difference between a small molecule bound to the protease in solution, and a small molecule alone in solution. Large negative binding free energies correspond to molecules that tightly bind to the protein, and thus can effectively stop the viral protein from functioning.

Docking is the process of bringing together two objects. For example, a ship docks with a pier in a harbor. Molecular docking refers to a computer simulation in which two molecules are brought together. In our case, we dock a "small" molecule (i.e., a possible drug) to a target molecule (i.e., the viral NS3 protease). A docking program predicts the orientation or pose of the small molecule when bound to the target. This is accomplished by maximizing favorable interactions and minimizing unfavorable interactions between the two molecules. In addition, the program gives each pose a score based on these interactions and the conformation of the small molecule.

Virtual screening is the process of systematically screening a database of small molecules against a defined target molecule. The scores provided by the docking programs rank how well the small molecule docks to the target protein relative to other molecules in the database. Unfortunately, these rankings typically produce a large number of false positives. In this project, binding free energy calculations, combined with docking scores, will provide an accurate prediction of compounds that most strongly bind to the target protease.

Some scientists refer to viruses as "cellular parasites." Viruses are composed of a protein coat and the genetic material (RNA or DNA) that encodes the proteins needed for replication. They are dependent on a host cell and the cellular machinery for translation of the genetic material into those proteins. Without a cell, the virus cannot replicate.

This study is addressing viruses that belong to the family Flaviviridae. This includes dengue fever, West Nile virus, yellow fever, Hepatitis C, Japanese encephalitis and others. See the FAQ: "What types of viruses belong to the family called Flaviviridae?"

The viruses that belong to the family Flaviviridae include three genera: the flaviviruses, the hepaciviruses, and the pestiviruses. The two genera on which this project focuses include the flaviviruses and the hepaciviruses. The genus flavivirus includes (but is not limited to) the mosquito-borne Dengue, West Nile virus, and Yellow Fever virus. It also includes the tick-borne encephalitis viruses. The genus hepacivirus includes Hepatitis C virus.

Cryo-electron microscopy is one way to determine the approximate structure of a virus or large protein. After isolating and concentrating particles, one can quickly freeze them on a microscope grid. The freezing allows the particles to be preserved "intact." Images of the particles on the grid are then obtained with an electron microscope. By reconstructing thousands of images, one can obtain a final three-dimensional structure with enough detail to observe the entire virus particle, as well as the individual structural proteins that comprise the particle.

Another method of obtaining virus and protein structures is X-ray crystallography. For this method, virus (or the viral protein of interest) is isolated, purified, concentrated, and crystallized. High-powered X-rays are beamed onto the crystal, and the diffraction pattern is analyzed computationally and ultimately reveals a structure of the molecule of interest.

While the flaviviruses and the hepaciviruses have some differences in their genome and coding strategies, the proteins they encode are very similar. They all encode the structural proteins that surround the nucleic acids. These include the envelope glycoproteins, the capsid protein, and the membrane protein. In addition, they encode non-structural proteins. These include a helicase, polymerase, methyl transferase, and the protease. It is the highly conserved protease that is the target of inhibition for this study.

About half of the antiviral drugs that exist are targeted against HIV. These include protease inhibitors, reverse-transcriptase inhibitors, nucleotide and non-nucleotide analogs, and a fusion inhibitor. There are a few antiviral drugs that target herpes virus, including nucleotide analogs and drugs that disrupt virus uncoating. There are also a few drugs that target influenza virus, cytomegalovirus, and hepatitis B virus. Many of these drugs have very limited efficacy.

Finding drugs that can be used safely remains one of the major difficulties in producing new drugs. Millions of compounds may need to be screened to discover a handful of compounds with a desired activity. Unfortunately, many compounds that show activity are either toxic or poorly absorbed in the human body. Since it is difficult to accurately predict the behavior of drug leads in the human body, perhaps only 1% of drug leads eventually become drugs.

Here is a video capture of the Discovering Dengue Drugs - Together - Phase 2 graphics:

You may get them by clicking the links for the resolutions below of the example screen shot.

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This is a picture of the drug candidate molecule your computer is analyzing at the current time. The spheres represent atoms in the molecule.

This provides some information about the name of the work unit being processed and the points the member has accrued.

This shows the approximate graphical and percentage value of how far along the processing of the current work unit has progressed. When it reaches 100% the computation should be completed and the results would then be sent back to the servers at World Community Grid.